Pyrimidine derivative having antimalarial activity

ABSTRACT

The present invention provides a novel 2,4,6-substituted pyrimidine derivative, which is a compound represented by formula (I) (in the formula, ring A is a 6-membered heteroaryl group having at least one N atom optionally substituted with R1, R2, and R3; Z is an optionally substituted alkoxy group, an optionally substituted amino group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group; and R1, R2, and R3 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted heterocycloalkyloxy group, an optionally substituted phenoxy group, an optionally substituted amino group, a nitro group, and a hydroxy group) or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel pyrimidine derivative, morespecifically to a 2,4,6-substituted pyrimidine derivative. The presentinvention has an action of inhibiting the growth of Plasmodium speciesand thus can be useful for the treatment, prevention and/or inhibitionof propagation of Plasmodium infection.

BACKGROUND ART

Malaria is a protozoan infection widely distributed in tropical tosubtropical regions. About 80% of the patients with malaria is infectedwith Plasmodium falciparum, a Plasmodium species parasitic on humans,and this is a very dangerous infection causing death in serious cases.Furthermore, due to recent global warming, malaria is not only endemicin developing countries in tropical and subtropical regions but alsoseems to be spreading in developed countries in temperate regions.

For Plasmodium species parasitic on humans, chloroquine and fansidar (adrug combination of pyrimethamine and sulfadoxin), which are called atraditional drug and were developed in the 1930s to the 1960s, have beenused. Later, artemisinin derivatives, an active ingredient of Artemisiaannua, a herbal drug, was developed after the 1980s, and have been used.

However, Plasmodium resistant to chloroquine and/or fansidar andPlasmodium resistant to a multidrug containing those have emerged. Thereis also a report on the emergence of protozoa resistant even toartemisinin derivatives which was developed later.

In response to the emergence of such protozoa resistant to existingdrugs, antimalarials effective for Plasmodium species have beendeveloped worldwide. However, in the development of antimalarials, inmany cases the antimalarial activity identified in vitro cannot beidentified in vivo, or drugs are found to be toxic, and thus few drugshave been found to be effective for drug-resistant strains and haveantimalarial activity in vivo.

Heretofore 2,4,5-substituted pyrimidine derivatives (Non patent document1 and Patent document 1) and 2,4,6-substituted pyrimidine derivatives(Non patent document 2) have been reported as a substance havingantimalarial activity, but no compounds are known to have the structureof the compound of the present invention.

PRIOR ART DOCUMENT(S) Patent Document(s)

-   [Patent document 1] WO2015/165660

Non-Patent Document(S)

-   [Non-patent document 1] Shahul Hameed P. et al., Nat. Commun.    6:6715, 2015.-   [Non-patent document 2] Xianming Deng, et al., Bioorg. Med. Chem.    Lett. 20: 4027-4031, 2010.

DISCLOSURE OF INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a novel compound whichshows antimalarial activity even on Plasmodium species resistant toexisting antimalarial.

Means for Solving Problem

The present inventors have conducted intensive studies to achieve theabove object, and as a result have found that the compound representedby Formula (I), i.e., a 2,4,6-substituted pyrimidine derivative, and apharmaceutically acceptable salt thereof (hereinafter may be referred toas “the compounds of the present invention”) have the action ofinhibiting growth of Plasmodium, and have completed the presentinvention. According to the present invention, propagation of infectionwith human infectious Plasmodium such as Plasmodium falciparum,Plasmodium vivax (P. vivax), Plasmodium malariae (P. malariae),Plasmodium ovale (P. ovale) and Plasmodium knowlesi (P. knowlesi) can betreated, prevented and/or inhibited.

The present invention includes following embodiments;

[1] A compound of the formula (I):

wherein the ring A is a 6-membered heteroaryl having one or morenitrogen atom(s) optionally substituted with R¹, R² and R³,

Z is an optionally substituted alkoxy group, an optionally substitutedamino group, optionally substituted heterocycloalkyl group, or anoptionally substituted heteroaryl group, and

R¹, R² and R³ are, each independently, selected from a group consistingof a hydrogen atom, a halogen atom, an optionally substituted alkylgroup, an optionally substituted cycloalkyl group, an optionallysubstituted alkoxy group, an optionally substituted cycloalkyloxy group,an optionally substituted heterocycloalkyloxy group, an optionallysubstituted phenoxy group, an optionally substituted amino group, anitro group, and a hydroxy group,

or pharmaceutically acceptable salt thereof,

[2] The compound of the formula (I) according to [1] above, wherein thering A is an optionally substituted 6-membered heteroaryl groupcontaining a nitrogen atom, or pharmaceutically acceptable salt thereof,

[3] The compound of the formula (I) according to [1] above, wherein thering A is an optionally substituted 6-membered heteroaryl groupcontaining two nitrogen atoms, or pharmaceutically acceptable saltthereof,

[4] The compound according to [1] above, wherein the group of

is a heteroaryl group selected from a group consisting of

or pharmaceutically acceptable salt thereof,[5] A compound of the general formula (I),

wherein the ring A is a heteroaryl group containing one or more nitrogenatom(s) optionally substituted with R¹, R² and R³,

Z is

wherein R⁴ and R⁵ are, each independently a hydrogen atom, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a —C₀₋₄ alkylene-CO—C₁₋₆ alkyl group, a—C₁₋₄ alkylene-O—C₁₋₆ alkyl group, a —C₁₋₄ alkylene-NH—C₁₋₆ alkyl group,a —C₁₋₄ alkylene-NH—CO—C₁₋₆ alkyl group, a —C₁₋₄ alkylene-NH—COO—C₁₋₆alkyl group, a —C₁₋₄ alkylene-N (the same or different C₁₋₆ alkyl)₂,—C₀₋₄ alkylene-COOH, a —C₀₋₄ alkylene-COO—C₁₋₆ alkyl group, —C₀₋₄alkylene-CH═NH, a —C₀₋₄ alkylene-CH═N—C₁₋₆ alkyl group, —C₀₋₄alkylene-SO₂H, a —C₀₋₄ alkylene-SO₂—C₁₋₈ alkyl group, a —C₀₋₄alkylene-(5-, or 6-membered heterocycloalkyl group), a —C₀₋₄alkylene-C₆₋₁₀ aryl group, or a —C₀₋₄ alkylene-(5-, or 6-memberedheteroaryl group),

wherein the alkyl group, the alkenyl group, the heterocycloalkyl group,the aryl group, the heteroaryl group and the alkylene group may beindependently substituted on a carbon atom which can be substituted,with a substituent or two or more substituents, the same or different,selected from a group consisting of a halogen atom, a C₁₋₆ alkyl group,a C₁₋₆ haloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, aC₃₋₈ cycloalkyl group, a hydroxy group, a mercapto group, a cyano group,a nitro group, an amino group, a mono- or di-C₁₋₆ alkyl-amino group, acarboxyl group, a C₁₋₄ acyl group and a C₁₋₄ acylamino group,

or R⁴ and R⁵ together with a nitrogen atom which they bound, may form a3- to 12-membered heterocycloalkyl group or a 5- or 6-memberedheteroaryl group,

R⁶ is a hydrogen atom, a C₁₋₈ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₈cycloalkyl group, a C₃₋₈ heterocycloalkyl group or a C₆₋₁₀ aryl group,each group may be substituted on a position which can be substituted,with a substituent or two or more substituents, the same or different,selected from a group consisting of a halogen atom, a C₁₋₆ alkyl group,a C₁₋₆ haloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, aC₃₋₈ cycloalkyl group, a hydroxy group, a mercapto group, a cyano group,a nitro group, an amino group, a mono- or di-C₁₋₆ alkyl-amino group, acarboxy group, a C₁₋₄ acyl group and a C₁₋₄ acylamino group, and

R¹, R² and R³ are independently selected from a group consisting of ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,an amino group, a mono- or di-C₁₋₆ alkyl-amino group, a nitro group, ahydroxy group, a C₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyloxy group, a 3-to 6-membered heterocycloalkyl group, a 3- to 6-memberedheterocycloalkyloxy group, a phenoxy group and a C₁₋₄ acylamino group,each group may be substituted on a position which can be substituted,with a substituent, or two or more substituents, the same or different,selected from a group consisting of a halogen atom, a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a C₁₋₆ haloalkyl group, a C₁₋₆ alkoxy group, aC₁₋₆ haloalkoxy group, a C₃₋₆ cycloalkyl group, a phenyl group, ahydroxy group, a mercapto group, a cyano group, a nitro group, an aminogroup, a mono- or di-C₁₋₆ alkyl-amino group, a carboxy group, a C₁₋₄acyl group, a C₁₋₄ acylamino group and a 5- or 6-memberedheterocycloalkyl group,

or pharmaceutically acceptable salt thereof,

[6] The compound according to any of [1] to [5] above, wherein Z isselected from a group of amino, C₁₋₆ alkoxy, and

wherein each group may be substituted on a position which can besubstituted, with a substituent, or two or more substituents, the sameor different, selected from a group consisting of a halogen atom, a C₁₋₆alkyl group, a C₁₋₆ haloalkyl group, a hydroxy group, a C₁₋₆hydroxyalkyl group, a C₁₋₆ alkoxy group, an amino group, a mono- ordi-C₁₋₆ alkyl-amino group, a carboxy group, a C₁₋₆ alkoxycarbonyl group,a 5- or 6-membered heterocycloalkyl group, a phenyl group, a benzylgroup, and a 5- or 6-membered heteroaryl group,or pharmaceutically acceptable salt thereof.[7] The compound according to any of [4] to [6], wherein the group of

two substituents of R¹, R² and R³ are hydrogen atoms, and the remainderis selected from a halogen atom, a hydroxy group, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₃₋₆ cycloalkyloxy group, a 3- to 6-memberedheterocyclo-alkyloxy group and a phenoxy group, which is linked to thepyridine at 2-, 4-, 5- or 6-position, and the C₁₋₆ alkyl group, C₁₋₆alkoxy group, C₃₋₆ cycloalkyloxy group, 3- to 6-memberedheterocyclo-alkyloxy group and phenoxy group may be substituted with oneor more group(s), the same or different, selected from the groupconsisting of a halogen atom, a hydroxy group, a C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a phenyl group, an amino group,a mono-C₁₋₆ alkyl amino group or a di-C₁₋₆ alkyl amino group and acarboxy group, at a position which can be substituted,

or pharmaceutically acceptable salt thereof.

[8] The compound according to any of [4] to [6], wherein the group of

one of R¹, R² and R³ is a hydrogen atom, and the remainders are selectedfrom a C₁₋₆ alkyl group and a C₃₋₆ cycloalkyl group, which are linked tothe pyridine ring at 4- and 6-, or 5- and 6-positions, and the C₁₋₆alkyl group and C₃₋₆ cycloalkyl group may be independently substitutedwith one or more group(s), the same or different, selected from thegroup consisting of a halogen atom, a hydroxy group, an amino group, anda mono-C₁₋₆ alkyl amino group or a di-C₁₋₆ alkyl amino group and acarboxy group, at a position which can be substituted,

or pharmaceutically acceptable salt thereof.

[9] The compound according to any of [4] to [6], wherein the group of

two of R¹, R² and R³ are hydrogen atoms, and the remainder is a halogenatom, a C₁₋₆ alkyl group, a nitro group, a C₁₋₆ alkoxy group or a C₃₋₆cycloalkyl group, which is linked to the pyridine ring at 3-, 4-, 5- or6-position, and the C₁₋₆ alkyl group, C₁₋₆ alkoxy group and C₃₋₆cycloalkyl group may be substituted with one or more group(s), the sameof different, selected from the group consisting of a halogen atom, ahydroxy group, a C₁₋₆ alkoxy group, an amino group, and a mono-C₁₋₆alkyl amino group or a di-C₁₋₆ alkyl amino group and a carboxy group, ata position which can be substituted,

or pharmaceutically acceptable salt thereof.

[10] The compound according to any of [4] to [6], wherein the group of

R¹, R² and R³ are independently selected from the group of a halogenatom, a C₁₋₆ alkyl group and a C₃₋₆ cycloalkyl group, which are linkedto the pyridine ring at 4-, 5- and 6-positions, and the C₁₋₆ alkyl groupand C₃₋₆ cycloalkyl group may be substituted with one or more group(s),the same of different, selected from the group consisting of a halogenatom, a hydroxy group, an amino group, and a mono- or di-C₁₋₆ alkylaminogroup and a carboxy group, at a position which can be substituted,

or pharmaceutically acceptable salt thereof,

[11] The compound according to any of [4] to [6], wherein the group of

and

R¹, R² and R³ are hydrogen atoms,

or pharmaceutically acceptable salt thereof.

[12] A pharmaceutical composition comprising the compound according toany of [1] to [11] or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

[13] A therapeutic agent for treating infection diseases of malariaplasmodium, comprising the compound according to any of [1] to [11] or apharmaceutically acceptable salt thereof.

[14] Method for treating infection diseases of malaria plasmodium in apatient in need of such treatment, characterized in administrating atherapeutically effective amount of the compound according to any of [1]to [11] or a pharmaceutically acceptable salt thereof.[15] The compound according to any of [1] to [11] or a pharmaceuticallyacceptable salt thereof for use in treating infection diseases ofmalaria plasmodium.[16] Use of the compound according to any of [1] to [11] or apharmaceutically acceptable salt thereof for manufacturing a medicinefor treating infection diseases of malaria plasmodium.[17] An inhibitor for proliferation of malaria plasmodium comprising thecompound according to any of [1] to [11] or a pharmaceuticallyacceptable salt thereof.[18] Method for inhibiting proliferation of malaria plasmodium,characterized in administrating a therapeutically effective amount ofthe compound according to any of [1] to [11] or a pharmaceuticallyacceptable salt thereof.

Effects of Invention

A compound of the present invention has an activity of inhibitingproliferation of malaria plasmodium, and is useful as a noveltherapeutic agent, preventing and/or inhibiting agent for propagation ofinfection disease caused by malaria plasmodium. Also it is useful as atherapeutic agent, preventing and/or inhibiting agent for treatinginfection disease of malaria plasmodium, which is tolerant to knownanti-malaria agents such as chloroquine and sulfadoxine/pyrimethamine(fansidar). Moreover, it is useful as a reagent of experimental orlaboratory use for inhibiting proliferation of malaria plasmodium.

BEST MODE FOR CARRYING OUT THE INVENTION

Terms used in this specification are explained as follows; “Halogenatom” means a fluorine atom, a chlorine atom, a bromine atom or aniodine atom. A fluorine atom, a chlorine atom and/or a bromine atom arepreferable among them.

“Alkyl” or “alkylene” means a monovalent and divalent saturatedhydrocarbon groups respectively, having a straight or branched carbonchain with pre-determined number of carbon atoms. It may be substitutedwith one or more substituent(s) included in this application, ifnecessary, at a position which can be substituted. Preferable examplesof the alkyl include C₁₋₆ alkyl, C₁₋₄ alkyl and a lower alkyl. Forexample, “C₁₋₆ alkyl” means alkyl having 1 to 6 carbon atom(s), and“lower alkyl” means alkyl having 1 to 4 carbon atom(s). “Co alkylene”means a single bond, and “C₁₋₄ alkylene” means a divalent group having 1to 4 carbon atom(s) such as methylene, ethylene, propylene and butyleneetc. Non-limiting examples of alkyl include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl andhexyl etc.

“Alkenyl” means an unsaturated hydrocarbon group including one or moreof carbon-carbon double bond(s), having a straight or branched carbonchain with pre-determined number of carbon atoms. It may be substitutedwith one or more substituent(s) included in this application, ifnecessary, at a position which can be substituted. Examples of preferredalkenyl include C₂₋₆ alkenyl or C₂₋₄ alkenyl. For example, “C₂₋₆alkenyl” means alkenyl having 2 to 6 carbon atoms. Non-limiting examplesof alkenyl include ethenyl, propenyl, butenyl, pentenyl, hexenyl etc.

“Haloalkyl” means the alkyl group defined above with pre-determinednumber of carbon atom(s), in which one or more of hydrogen atom(s) arereplaced with halogen atoms. For example, “C₁₋₆ haloalkyl” meanshaloalkyl having 1 to 6 carbon atom(s). A range of numbers of replacedhydrogen atoms can be from 1 to the total number of hydrogen atomsexisting in the parent alkyl group. The alkyl may be substituted withthe same or different halogen atoms when two or more hydrogen atoms aresubstituted. Non-limiting examples of haloalkyl include chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl etc.

“Hydroxyalkyl” means hydroxy to which the alkyl defined above havingpredetermined number of carbon atoms were connected. The alkyl moietymay be substituted with one or more substituent(s) included in thepresent invention. Examples of the preferred hydroxyalkyl include C₁₋₆hydroxyalkyl and C₁₋₄ hydroxyalkyl. For example, “C₁₋₆ hydroxyalkyl”means hydroxyalkyl having 1 to 6 carbon atom(s). Non-limiting examplesof the hydroxyalkyl include hydroxymethyl and hydroxyethyl etc.

“Alkoxy” means a group in which the above defined alkyl withpredetermined number of carbon atoms is connecting through an oxygenatom. The alkyl moiety may be substituted with one or moresubstituent(s) included in the present invention. Examples of thepreferred alkoxy include C₁₋₆ alkoxy and C₁₋₄ alkoxy. For example, “C₁₋₆alkoxy” means alkoxy (—O—C₁₋₆ alkyl) having 1 to 6 carbon atom(s).Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy,isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxyetc.

“Haloalkoxy” means the above defined alkoxy with predetermined number ofcarbon atoms, in which one or more hydrogen atom(s) are replaced withhalogen atom(s). For example, “C₁₋₆ haloalkoxy” means haloalkoxy having1 to 6 carbon atoms. A range of numbers of replaced hydrogen atoms canbe from 1 to the total number of hydrogen atoms existing in the parentalkyl group. The alkoxy may be substituted with same or differenthalogen atoms when two or more hydrogen atoms are substituted.Non-limiting examples of haloalkoxy include chloromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy etc.

“Cycloalkyl” means monocyclic or multicyclic saturated hydrocarbonhaving three or more carbon atoms, and it may be substituted with asubstituent included in the present invention, if necessary, at aposition which can be substituted. Examples of preferred cycloalkylinclude C₃₋₁₀ cycloalkyl, C₃₋₈ cycloalkyl, and C₃₋₆ cycloalkyl. Forexample, “C₃₋₈ cycloalkyl” means cycloalkyl having 3 to 8 carbon atoms.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl etc. but they are not limited tothese examples. Examples of multicyclic saturated hydrocarbon includebicyclic saturated hydrocarbon and tricyclic saturated hydrocarbon, anddecahydronaphthalene, bicyclo[2.1.0]pentane,tricyclo[3.2.1.0^(2,7)]octane etc. are exemplified.

“Heterocycoalkyl” means the cycloalkyl defined above, in which at leastone ring carbon is replaced with a heteroatom selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom, and itmay be substituted with one or more substituent(s) included in thepresent invention, if necessary, at position(s) which can besubstituted. Also, the nitrogen atom and/or the sulfur atom may beoxidized and the nitrogen atom may be quaternized, if necessary. Inbicyclic heterocycloalkyl, one of the fused ring may contain only carbonatoms, and a saturated, partially saturated and/or unsaturated ring maybe included. Examples of preferred heterocycloalkyl include 3- to10-membered heterocycloalkyl, 3- to 8-membered heterpcycloalkyl, 3- to6-membered heterocycloalkyl and the like. For example, “3- to 8-memberedheterocycloalkyl” means 3- to 8-membered cycloalkyl containing at leastone heteroatom selected from a nitrogen atom, an oxygen atom and asulfur atom. Non-limiting examples of heterocycloalkyl includesaziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, homopiperidine, tetrahydrofuran, tetrahydropyran,oxazolidinone, 2-azaspiro[4.4]nonane, 8-oxa-2-azaspiro[4.5]decane,hexahydropenta[c]pyrrole, 2-oxa-6-azaspiro[3.3]heptane,tetrahydro-2H-[1.4]dioxino[2,3-c]pyrrole etc.

“Aryl” means a monocyclic or bicyclic aromatic hydrocarbon group havingsix or more carbon atoms, in which one hydrogen atom on the aromaticring is excluded, and it may be substituted with one or moresubstituent(s) included in the present invention, if necessary, atposition(s) which can be substituted. Non-limiting examples of preferredaryl include C₆₋₁₀ aryl. Examples of aryl include phenyl, 1-naphthyl,2-naphthyl, anthracenyl etc.

“Heteroaryl” means a monocyclic or bicyclic aromatic heterocyclo groupcontaining at least one heteroatom selected from the group consisting ofa nitrogen atom, an oxygen atom and a sulfur atom, and it may besubstituted with one or more substituent(s) included in the presentinvention, if necessary, at position(s) which can be substituted.Examples of preferred heteroaryl include 3- to 10-membered heteroaryl,3- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl. Forexample, “5- to 6-membered heteroaryl” means 5- and 6-memberedmonocyclic heterocyclo group containing at least one heteroatom selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom. Non-limitingexamples of heteroaryl include thiophen, furan, pyrrole, imidazole,pyrazole, thiazole, oxazole, isothiazole, isooxazole, pyridine,pyrimidine, pyrazine, pyridazine, triazine, indole, purin, quinoline,isoquinoline etc.

“Acyl” means carbonyl group [—C(═O)] connected to a hydrogen atom orabove-defined alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl.Examples of preferred acyl include C₁₋₇ acyl, and C₁₋₄ acyl. Forexample, “C₁₋₄ acyl” means carbonyl group connected to an alkyl grouphaving 1 to 3 carbon atom(s). Non-limiting examples of acyl includeformyl, acetyl, propanoyl, butyryl, pivaloyl, cyclopentanecarbonyl,benzoyl etc.

“Acylamino” means an amino group connected to the acyl group definedabove, and examples of preferred acylamino include C₁₋₇ acylamino, C₁₋₄acylamino. For example, “C₁₋₄ acylamino” means an amino group connectedto acyl having 1 to 4 carbon atom(s). Non-limiting examples of acylaminoinclude acetylamino, propionylamino etc.

“Mono- or di-C₁₋₆ alkylamino” means an amino group in which one or twohydrogen atom(s) are replaced with C₁₋₆ alkyl defined above, and it maybe substituted with the same or different alkyl groups when substitutedwith two alkyl groups. Non-limiting examples of mono- or di-C₁₋₆alkylamino include methylamino, ethylamino, dimethylamino anddiethylamino etc.

“Alkoxycarbonyl” means a carbonyl group to which the above-definedalkoxy is connected. Examples of preferred alkoxycarbonyl include C₁₋₆alkoxycarbonyl, and C₁₋₄ alkoxycarbonyl. For example, “C₁₋₆alkoxycarbonyl” means a carbonyl group to which an alkoxy group having1- to 6-carbon atoms is connected. Non-limiting examples ofalkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, and hexyloxycarbonyl etc.

“Optionally substituted” means a case in which the position is notsubstituted (non-substituted) and a case in which it is substituted at aposition which can be substituted. “Non-substituted” means all positionswhich can be substituted are hydrogen atoms. When substituted, it may besubstituted with two or more substituent, if possible, and thesubstituents may be the same or different from each other. Examples ofthe substituent include a halogen atom, an alkyl group, an alkenylgroup, a cycloalkyl group, a heterocycloalkyl group, a haloalkyl group,an alkoxy group, a haloalkoxy group, an amino group, a nitro group, acyano group, a hydroxy group, a mono- or di-alkylamino group, acarbamoyl group, a carboxyl group, a morpholinyl group, a formyl group,an acetyl group, a mesyl group, a benzoyl group, an acylamino group, abenzyl group, an aryl group, a heteroaryl group etc.

“Pharmaceutically acceptable salt” means a salt formed by a compound ofthe formula (I) in the present invention and a pharmaceuticallyacceptable acid or base. When the compound of the formula (I) in thepresent invention has a basic functional group such as an amino group,it is possible to form a salt with a variety of acids. Examples of anacid-addition salt include a non-organic acid salt such ashydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate andphosphate etc., an organic acid salt such as oxalate, malonate, maleate,fumarate, lactate, malate, citrate, tartrate, benzoate,trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate andtrifluoromethanesulfonate, and an acidic amino acid salt such asglutamate, and aspartate.

When the compound of the formula (I) in the present invention has anacidic functional group, it is possible to form a salt with a variety ofbases. Examples of a base-addition salt include an alkali metal saltsuch as a sodium salt and a potassium salt, an alkali earth metal saltsuch as a calcium salt, an organic amine salt such as a lower alkylamine salt and a lower alcohol amine salt, a basic amino acid salt suchas a lysine salt, an arginine salt and an ornithine salt, and anammonium salt.

These salts can be prepared in a conventional manner such asrecrystallization etc. after mixing the compound of the formula (I) inthe present invention with an acid or base.

A compound of the present invention may be obtained as an inner salt, ahydrate and/or a solvate, and these inner salt, hydrate and solvate arealso included in the present invention. Examples of the solvate includean ethanol solvate.

“Treatment” means healing and/or improvement of infection diseasescaused by malaria plasmodium in mammals, especially human. For example,it is included (a) to prevent infection diseases caused by malariaplasmodium; (b) to inhibit propagation of infection disease caused bymalaria plasmodium; and (c) to alleviate and/or reduce infection diseasecaused by malaria plasmodium.

“Patient” means human and animals such as a dog, a cat and a horse etc.,and among them, human is preferable.

“Effective amount for treatment” means an amount for improvement,healing, prevention and/or reduction of a disease, a disorder and/or aside effect compared with an untreated patient, or an amount forretarding progression of a disease and/or a disorder. Said term alsoincludes an effective amount for enhancing normal physiologicalfunctions. An effective amount of a compound of the formula (I) in thepresent invention may be administered as an unformulated bulk. Usually,a range from about 1 to about 1,000 mg/kg (body weight) of a compound ofthe formula (I) is effective, but the effective amount is not limitedthereto.

Examples of the effective amount include an amount of the compound inthe present invention alone, an amount of a combination of the compoundsin the present invention and an amount of the compound of the presentinvention in a combination with other anti-malarial agent(s).

A preferred embodiment of the ring A is a 6-membered heteroaryl grouphaving one or more nitrogen atom(s) optionally substituted with R¹, R²and R³, and a more specific embodiment of the ring A is a heteroarylgroup selected from the group consisting of

A preferred embodiment of Z is a group selected from the groupconsisting of an amino group, C₁₋₆ alkoxy group,

and each group may be substituted with one or more substituent(s), thesame or different, selected from the group consisting of a halogen atom,a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a hydroxy group, a C₁₋₆hydroxyalkyl group, a C₁₋₆ alkoxy group, an amino group, a mono- ordi-C₁₋₆ alkylamino group, a carboxy group, a C₁₋₆ alkoxycarbonyl group,a 5- or 6-membered heterocycloalkyl group, a phenyl group, a benzylgroup and a 5- or 6-membered heteroaryl group at a position which can besubstituted.

A preferred embodiment of R¹ to R³ is a hydrogen atom, a halogen atom, ahydroxy group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, aC₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyloxy group, a 3- to 6-memberedheterocyclo-alkyloxy group, or a phenoxy group, wherein

the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, the C₃₋₆ cycloalkyl group,the C₃₋₆ cycloalkyloxy group, the 3- to 6-membered heterocycloalkyloxygroup, and the phenoxy group may be independently substituted with oneor more substituent(s), the same or different, selected from the groupconsisting of a halogen atom, a hydroxy group, an amino group, a mono-or di-C₁₋₆ alkylamino group, carboxy group, C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₁₋₆ alkoxy group and a phenyl group at a positionwhich can be substituted.

A more preferred embodiment of R¹ to R³ is a hydrogen atom, a fluorineatom, a chlorine atom, a hydroxy group, a nitro group, a methyl group,an ethyl group, an isopropyl group, a butyl group, an isobutyl group, atert-butyl group, a neopentyl group, a fluoromethyl group, atrifluoromethyl group, a hydroxymethyl group, an ethoxymethyl group, apropoxymethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a methoxy group,an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,an isobutoxy group, a neopentyloxy group, a difluoromethoxy group, atrifluoroethoxy group, a 2-(dimethylamino)ethoxy group, an allyloxygroup, a 2-methoxyethoxy group, a 2-(tert-butoxy)ethoxy group, a2-morpholinoethoxy group, a 2-hydroxyethoxy group, a benzyloxy group, acyclopropyl group, a cyclobutoxy group, a cyclohexyloxy group, a(1-methylpiperidin-4-yl)oxy group, a (tetrahydro-2H-pyran-4-yl)oxy groupor a phenoxy group.

A compound of the formula (I) or an intermediate of the presentinvention can be separated and purified with a method known to a skilledperson in the art. For example, an extraction, a distribution, are-precipitation, a column chromatography such as a silica gel columnchromatography, an ion-exchange column chromatography or a preparativeliquid chromatography and a recrystallization etc. are exemplified.

A compound of the formula (I) of the present invention may have one ormore asymmetric carbon(s), or include geometric isomerism or axialchirality, and several kinds of optical isomers or stereoisomers may beprovided. These optical isomers or stereoisomers, a mixture thereof anda racemate are included in the compound of the formula (I) of thepresent invention.

A compound of the formula (I) of the present invention may have anisomer depending on a structure of its substituent, for example. Thepresent invention include every possible isomer (a geometric isomer, anoptical isomer and a tautomer etc.), and not only an isolated isomer,but a mixture of isomers are included therein, though only one chemicalstructure of the single isomer is described in this specification.

Further a deuterated compound of the formula (I) in the presentinvention in which one or more ¹H are replaced with ²H(D) is alsoinclude therein.

A compound of the formula (I) or its pharmaceutical salt of the presentinvention may have crystalline polymorph, which is also included in thepresent invention.

A compound of the present invention or pharmaceutically acceptable saltthereof can be prepared, for example, according to methods describedbelow. When a group defined in the formula may be changed under thedescribed conditions or is improper for the chemical reaction, thedesired product may be easily obtained by using a means which is commonin an organic synthesis such as a protection and a de-protection of afunctional group [T. W. Greene, Protective Groups in Organic Synthesis3rd Edition, John Wiley & Sons, Inc., 1999]. Also it is possible tochange an order of processes introducing a substituent etc., ifnecessary.

Meanings of abbreviations and symbols used in the following descriptionare as follows.

THF: Tetrahydrofuran

NMP: N-methyl pyrrolidone

2-PrOH: 2-propanol

DIEA: N,N-diisopropyl ethylamine

DMSO: Dimethyl sulfoxide

DMF: Dimethylformamide

TEA: Triethylamine

MeOH: Methanol

EtOH: Ethanol

CHCl₃: Chloroform

CDCl₃: Heavy chloroform

DCM: Dichloromethane

RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

BrettPhos:2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl

Xantphos: 4,5-Bis(diphenyl phosphino)-9,9-dimethyl xanthene

Pd(dba)₂: Bis(dibenzylideneacetone)palladium(0)

[Method for Preparing a Compound of the Formula (I) in the PresentInvention]

A compound of the formula (I) of the present invention can be preparedaccording to scheme 1, for example:

wherein the ring A, R¹, R², R³ and Z are the same as described before.

The compound (I) can be prepared by reacting a chloro compound (II) withimidazo[1,2-a]pyrdine-7-amine under the condition of a cross-couplingreaction such as Buchwald/Hartwig type reaction. Specifically, thereaction is carried out by using a palladium catalyst such as Pd(dba)₂,a base such as sodium tert-butoxide, potassium carbonate, and cesiumcarbonate and a ligand such as RuPhos, BrettPhos, Xantphos in an inertsolvent such as toluene, THF or dioxane. It is preferable to useequivalent or excess amount of imidazo[1,2-a]pyrdine-7-amine comparedwith the chloro compound (II), and 1 to 10 equivalent is morepreferrable. The product is synthesized by the reaction for a fewminutes to a few days at 0° C. to 200° C., preferably for 1 hour to 36hours at 20° C. to 150° C. It is also possible to synthesize the productby reacting under the temperature condition of from 60° C. to 150° C.for several minutes to several hours, using a microwave synthesisequipment.

The chloro compound (II) which is used in scheme 1 as a startingmaterial can be prepared according to scheme 2, for example:

wherein the ring A, R¹, R², R³ and Z are the same as described before.

The chloro compound (II) can be prepared by heating and reacting 0.8 to5 mole equivalent, preferably 0.8 to 1 mole equivalent of the compound(IV) with the dichloro compound (III) in a solvent. If necessary, anacid catalyst such as hydrochloric acid, or a base may be added to thereaction, and any solvent may be used if the reaction is not disturbed,but a polar solvent such as DMF or THF is preferable. When the compound(IV) is a liquid and the reacting point is an alcoholic hydroxy group,the compound (IV) itself may be used as a solvent. The reaction can becarried out by stirring the reaction mixture for 3 to 24 hours at roomtemperature to a refluxing condition of the solvent.

The compound (IV) which is one of starting materials in scheme 2 can beobtained as a commercially available product, or can be obtained by awell-known procedure or the procedure according to it.

The dichloro compound (III) can be prepared according to scheme 3, forexample;

wherein the ring A, R¹, R² and R³ are the same as described before.

The dichloro compound (III) can be prepared by reacting4,6-dichloro-2-(methylsulfonyl)pyrimidine (V) with the amine (VI).Specifically, The dichloro compound (III) can be obtained by reacting0.5 to 5 mole equivalent, preferably 1.2 to 2.0 mole equivalent of theamine (VI) with 4,6-dichloro-2-(methylsulfonyl)pyrimidine (V) in asolvent. If necessary, an acid catalyst such as hydrochloric acid, or abase may be added to the reaction, and any solvent may be used if thereaction is not disturbed, but a polar solvent such as THF or dioxane ispreferable. The reaction can be carried out by reacting for 1 to 24hours at −78° C. to a refluxing condition of the solvent, preferablyreacting for 0.5 to 2 hours at −78° C. to −70° C.

The amine (VI) which is one of starting materials in scheme 3 can beobtained as a commercially available product, or can be obtained by awell-known procedure or the procedure according to it.

The dichloro compound (III) can be also prepared by replacing4,6-dichloro-2-(methylsulfonyl)pyrimidine (V) with2,4,6-trichloropyrimidine in scheme 3 and reacting it in the samemanner.

The chloro compound (II) which is used in scheme 1 as a startingmaterial can be also prepared according to scheme 4, for example;

wherein the ring A, R¹, R², R³ and Z are the same as described before.

The chloro compound (II) can be prepared by reacting the compound (VII)with the amine (VI). Specifically, the chloro compound (II) can beobtained by reacting 0.5 to 2 mole equivalent, preferably 0.8 to 1.5mole equivalent of the amine (VI) with the compound (VII) in a solvent.If necessary, an acid catalyst such as hydrochloric acid, or a base maybe added to the reaction, and any solvent may be used if the reaction isnot disturbed, but a polar solvent, preferably an alcoholic solvent suchas EtOH or 2-PrOH, or dioxane or THF may be used. The reaction can becarried out by reacting for 1 to 24 hours at −40° C. to a refluxingcondition of the solvent, preferably reacting for 1 to 16 hours at roomtemperature to a refluxing condition of the solvent.

The compound (VII) which is used in scheme 4 as a starting material canbe obtained as a commercially available product, or can be obtained by awell-known procedure or the procedure according to it.

In addition, a compound of the present invention having a desiredfunctional group at a desired position can be prepared by a suitablecombination of the methods above, or a procedure usually carried out inan organic synthesis (for example, alkylation reaction of an aminogroup, oxidation reaction of an alkylthio group into a sulfoxide groupor a sulfone group, converting reaction of an alkoxy group into ahydroxy group, or opposite converting reaction thereof).

[Use of a Compounds of the Present Invention]

A compound (I) or a pharmaceutically acceptable salt thereof of thepresent invention can be prepared into a form of a conventionalpharmaceutical formulation (pharmaceutical composition), which is suitedfor oral administration, parenteral administration, or localadministration.

Formulations for oral administration include solid formulations such astablets, granules, powders, and capsules; and liquid formulations suchas syrups. These formulations can be prepared by a conventional method.The solid formulations can be prepared by using conventionalpharmaceutical carriers, for example, lactose; starches such as cornstarch; crystalline celluloses such as microcrystalline cellulose; andhydroxypropyl cellulose, calcium carboxymethyl cellulose; talc, andmagnesium stearate. Capsules can be prepared by encasing thus preparedgranules or powders in capsules. Syrups can be prepared by dissolving orsuspending the compound (I) or a pharmaceutically acceptable saltthereof of the present invention in an aqueous solution containingsucrose and carboxymethyl cellulose etc.

Formulations for parenteral administration include injections such asinstillation. Injection formulations can also be prepared by aconventional method, and can be appropriately incorporated into isotonicagents (for example, mannitol, sodium chloride, glucose, sorbitol,glycerol, xylitol, fructose, maltose, mannose), stabilizers (forexample, sodium sulfite, albumin), and antiseptics (for example, benzylalcohol, methyl p-oxybenzoate).

The dosage of the compound (I) or a pharmaceutically acceptable saltthereof of the present invention can vary depending on severity ofdisease, age and body weight of the patient, and dosage form, and isusually within a range from 1 mg to 1,000 mg per day for adults. Thecompound or a pharmaceutically acceptable salt thereof can beadministered once, or dividedly administered twice or three timesaccording to an oral or parenteral route.

A compound (I) of the present invention is useful for treating,preventing and/or inhibiting propagation of infection disease caused bymalaria plasmodium, which is tolerant to known anti-malaria agents suchas chloroquine and sulfadoxine/pyrimethamine (fansidar). Moreover, it isuseful as a reagent of experimental or laboratory use for inhibitingproliferation of malaria plasmodium.

EXAMPLES

The present invention will be more specifically described below by wayof Examples and Test Examples, but the present invention is not limitedto these Examples.

Identification of the compound was carried out by hydrogen nuclearmagnetic resonance spectrum (¹H-NMR) and mass spectrum (MS). ¹H-NMR ismeasured at 400 MHz, unless otherwise specified, and exchangeablehydrogen cannot be sometimes clearly observed depending on the compoundand measurement conditions. Abbreviation of “br.” means a broad signal(broad).

HPLC preparative chromatography was carried out by a commerciallyavailable ODS column in a gradient mode using water/methanol (containingformic acid) as eluents, unless otherwise specified.

Reference Example 1 Preparation of4-Chloro-N-(6-ethoxypyridin-3-yl)-6-morpholinopyrimidin-2-amine

(Process 1)

A THF solution (5 ml) of 5-amino-2-ethoxypyridine (0.5 g, 3.6 mmol) wascooled to −78° C., a THF solution of sodium bis(trimethylsilyl)amide(2M, 3 ml, 6.0 mmol) was added thereto and the mixture was stirred for10 minutes. A THF solution (5 ml) of4,6-dichloro-2-(methylsulfonyl)pyrimidine (0.548 g, 2.4 mmol) was addedto the reaction mixture, and the whole mixture was stirred for an hour.After confirming disappearance of the starting material, acetic acid andwater were added, and extracted with 50% ethyl acetate/hexane. Theobtained organic layer was dried over anhydrous sodium sulfate. Thesolvent was evaporated and the residue was purified with a columnchromatography (silica gel, ethyl acetate/hexane) to give4,6-dichloro-N-(6-ethoxypyridin-3-yl)pyrimidin-2-amine (0.325 g).

¹H-NMR (CDCl₃) δ(ppm): 8.25 (d, J=2.5 Hz, 1H), 7.84 (dd, J=2.9, 8.8 Hz,1H), 7.00 (br. s, 1H), 6.77-6.74 (m, 2H), 4.35 (q, J=7.3 Hz, 2H), 1.40(t, J=7.1 Hz, 3H); LCMS (m/z) 285.1[M+H]⁺.

(Process 2)

A DMF solution (5 ml) of4,6-dichloro-N-(6-ethoxypyridin-3-yl)pyrimidin-2-amine (0.325 g, 1.14mmol) was cooled to 0° C., sodium hydrogen carbonate (0.191 g, 2.28mmol) and morpholine (0.092 g, 105 mmol) were added thereto and themixture was stirred at room temperature for 16 hours. After confirmingdisappearance of the starting material, water was added, and extractedwith ethyl acetate. The obtained organic layer was dried over anhydroussodium sulfate. The solvent was evaporated and the residue was purifiedwith a column chromatography (silica gel, ethyl acetate/hexane) to givethe titled compound (0.28 g).

¹H-NMR (DMSO-d₆) δ(ppm): 9.36 (br. s, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.87(dd, J=2.7, 9.1 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.32 (s, 1H), 4.24 (q,J=6.9 Hz, 2H), 3.65-3.56 (m, 8H), 1.29 (t, J=6.9 Hz, 3H); LCMS (m/z)336.2[M+H]⁺.

Reference Example 2 Preparation of4-chloro-6-morpholino-N-(pyridin-4-yl)pyrimidin-2-amine

A catalytic amount of conc. hydrochloric acid was added to anisopropanol solution (10 ml) of 4-(2,6-dichloro-4-pyrimidinyl)morpholine(1.0 g, 4.27 mmol) and 4-aminopyridine (0.321 g, 3.41 mmol), and stirredat 90° C. for 16 hours. The precipitated solid was collected byfiltration, washed with isopropanol, methanol and ethyl acetatesuccessively, and a white crude product was obtained. The solid wasdissolved in 10% MeOH/DCM, and washed with water. The obtained aqueouslayer was condensed under reduced pressure, and the obtained solid waspurified with a column chromatography (silica gel, TEA/MeOH/DCM) to givethe titled compound (0.8 g).

¹H-NMR (CD₃OD) δ(ppm): 9.22-9.18 (m, 2H), 7.20-6.88 (m, 4H), 3.75-3.65(m, 8H); LCMS (m/z) 292.4[M+H]⁺.

Example 7 Preparation ofN2-(6-Ethoxypyridin-3-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4-diamine

A dioxane solution (7 ml) of the compound of Reference Example 1 (0.2 g.0.598 mmol), imidazo[1,2-a]pyridin-7-amine (0.119 g, 0.898 mmol) andsodium tert-butoxide (0.115 g, 1.19 mmol) was degassed, and Brettphospalladacycle G1 (0.048 g, 0.05 mmol) and Ruphos (0.028 g, 0.05 mmol)were added. The reaction mixture was further degassed by blowingnitrogen gas into it and the reaction was continued in a microwavereaction equipment at 110° C. for 30 minute. After confirmingdisappearance of the starting material, the reaction mixture wasfiltered with celite, and washed with 10% MeOH/DCM. The filtrate wascondensed under reduced pressure, and the obtained solid was purifiedwith a column chromatography (silica gel, MeOH/DCM) to give the titledcompound (0.05 g).

¹H-NMR (DMSO-d₆) δ(ppm): 9.16 (s, 1H), 8.90 (br. s, 1H), 8.38-8.33 (m,2H), 8.10-8.05 (m, 1H), 8.01 (dd, J=2.7, 9.1 Hz, 1H), 7.72 (s, 1H), 7.40(s, 1H), 7.05-7.00 (m, 1H), 6.78-6.70 (m, 1H), 5.56 (s, 1H), 4.25 (q,J=7.2 Hz, 2H), 3.70-3.67 (m, 4H), 3.45-3.43 (m, 4H), 1.29 (t, J=6.9 Hz,3H); LCMS (m/z) 433.3[M+H]⁺.

Examples 1-6 and 8-222

Each of the Example compounds shown in the following [Table 1-1] to[Table 1-40] were prepared according to the procedure described inExample 7 above or said procedure combined with a common method wellknown in the art of organic chemistry, if needed, using appropriatestarting materials (those materials are obtained from commercialsources, or are prepared by literature procedures or modifications ofliterature procedures known to persons skilled in the art).

The physicochemical data of each compound were shown in the following[Table 2-1] to [Table 2-41].

TABLE 1-1 Ex. Structure Name 1

N4-(Imidazo[1,2-a]pyridin-7- yl)-N2-(6-methoxypyridin-3-yl)-6-morpholinopyrimidine- 2,4-diamine 2

N2-(4,6-dimethylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine 3

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(pyridin-4-yl)pyrimidine-2,4-diamine dihydrochloride 4

N4-(Imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(pyridin-3-yl)pyrimidine-2,4-diamine 5

N4-(Imidazo[1,2-a]pyridin-7- yl)-N2-(2-methoxypyridin-3-yl)-6-morpholinopyrimidine- 2,4-diamine 6

N2-(5-Fluoropyridin-3-yl)-N 4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine

TABLE 1-2 8

N4-(Imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(pyrimidin-5-yl)pyrimidine-2,4-diamine 9

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(3-methylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine 10

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(6-methylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine 11

N2-(2-Fluoropyridin-3-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 12

N2-(6-Fluoropyridin-3-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 13

N2-(5-Fluoropyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 14

N2-(6-Fluoropyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine

TABLE 1-3 15

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(6-isopropoxypyridin-3-yl)-6-morpholinopyrimidine-2,4- diamine 16

N4-(Imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(pyrimidin-2-yl)pyrimidine-2,4-diamine 17

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(4-methylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine 18

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(5-methylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine 19

N4-(Imidazo[1,2-a]pyridin-7-yl)- N2-(5-methoxypyridin-3-yl)-6-morpholinopyrimidine-2,4- diamine 20

N2-(3-Fluoropyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 21

N2-(4-Fluoropyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine

TABLE 1-4 22

N4-(Imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(pyrimidin-4-yl)pyrimidine-2,4-diamine 23

N4-(Imidazo[1,2-a]pyridin-7- yl)-N2-(4-methoxypyridin-3-yl)-6-morpholinopyrimidine-2,4- diamine 24

5-(4-(Imidazo[1,2-a]pyridin-7- ylamino)-6-morpholinopyrimidin-2-ylamino)pyridin-2-ol 25

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(4-methylpiperazin-l-yl)-N2-(4-methylpyridin-2-yl)pyrimidine- 2,4-diamine 26

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(5-methylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 27

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(4-methylpiperazin-1-yl)-N2-(5-methylpyridin-2-yl) pyrimidine-2,4-diamine 28

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-methylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine

TABLE 1-5 29

6-ethoxy-N4-(imidazo[1,2-a] pyridin-7-yl)-N2-(6-methylpyridin-2-yl)pyrimidine-2,4-diamine 30

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(4-methylpiperazin-1-yl) pyrimidine-2,4-diamine 31

(S)-N2-(4,6-dimethylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(3-methylpiperazin-1- yl)pyrimidine-2,4-diamine 32

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 33

N2-(4,6-dimethylpyridin-2-yl)- 6-ethoxy-N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4- diamine 34

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-methylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 35

(S)-6-(3,4-dimethylpiperazin-1- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(4-methylpyridin-2- yl)pyrimidine-2,4-diamine

TABLE 1-6 36

6-ethoxy-N4-(imidazo[1,2-a] pyridin-7-yl)-N2-(4- methylpyridin-2-yl)pyrimidine-2,4-diamine 37

(S)-6-(3,4-dimethylpiperazin-1- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(5-methylpyridin-2- yl)pyrimidine-2,4-diamine 38

6-ethoxy-N4-(imidazo[1,2-a] pyridin-7-yl)-N2-(5-methylpyridin-2-yl)pyrimidine- 2,4-diamine 39

N4-(imidazo[1,2-a]pyridin- 7-yl)-6-(4-methylpiperazin-1-yl)-N2-(6-methylpyridin- 2-yl)pyrimidine-2,4- diamine 40

(S)-6-(3,4-dimethylpiperazin-1- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(6-methylpyridin-2- yl)pyrimidine-2,4-diamine 41

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(1H-imidazol-1-yl)-N2-(6-methylpyridin-2-yl)pyrimidine- 2,4-diamine 42

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(1H-imidazol-1-yl)-N2-(4-methylpyridin-2-yl)pyrimidine- 2,4-diamine

TABLE 1-7 43

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(1H-imidazol-1-yl)-N2-(5-methylpyridin-2-yl)pyrimidine- 2,4-diamine 44

N4-amidazo[1,2-a]pyridin-7- yl)-N2-(5-methylpyridin-2-yl)pyrimidine-2,4,6-triamine 45

(S)-6-(3,4-dimethylpiperazin-1- yl)-N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 46

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a[pyridin-7-yl)-6-(1H-imidazol-1-yl)pyrimidine- 2,4-diamine 47

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(4-(trifluoromethyl)pyridin-2-yl) pyrimidine-2,4-diamine 48

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-methoxypyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine

TABLE 1-8 49

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(4-nitropyridin-2-yl)pyrimidine- 2,4-diamine 50

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-methylpyridin-2-yl)pyrimidine-2,4,6-triamine 51

N2-(6-ethoxypyridin-3-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 52

(S)-6-(3,4-Dimethylpiperazin-1- yl)-N2-(6-ethoxypyridin-3-yl)-N4-(imidazo[1,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 53

N2-(4-Cyclopropyl-5-fluoro-6- methylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6- morpholinopyrimidine-2,4- diamine 54

N4-(Imidazo[1,2-a]pyridin-7- yl)-N2-(6-methylpyridin-2-yl)pyrimidine-2,4,6-triamine

TABLE 1-9 55

N4-(Imidazo[1,2-a]pyridin-7- yl)-N2-(6-isopropoxypyridin-3-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 56

(S)-6-(3,4-dimethylpiperazin-1- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(6-isopropoxypyridin- 3-yl)pyrimidine-2,4-diamine 57

6-Ethoxy-N4-(Imidazo[1,2-a] pyridin-7-yl)-N2-(6- isopropoxypyridin-3-yl)pyrimidine-2,4- diamine 58

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4,6-triamine 59

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isopropoxypyridin-3-yl)-6-(4-methylpiperazin-1-yl) pyrimidine-2,4-diamine 60

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-methylpyridin-3-yl)-6-morpholinopyrimidine-2,4- diamine

TABLE 1-10 61

N2-(6-(2-(dimethylamino)ethoxy) pyridin-3-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholino- pyrimidine-2,4-diamine 62

N2-(6-butoxypyridin-3-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 63

N2-(6-(tert-butoxy)pyridin-3- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 64

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isobutoxypyridin-3-yl)-6-morpholinopyrimidine-2,4- diamine 65

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(6-(neopentyloxy)pyridin-3- yl)pyrimidine-2,4-diamine 66

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-(2-methoxyethoxy)-pyridin-3-yl)-6-morpholino- pyrimidine-2,4-diamine

TABLE 1-11 67

N2-(4-(tert-butyl)pyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 68

N2-(4-ethylpyridin-2-yl)-N4-(imidazo [1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 69

N4-(imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(6-propoxy-pyridin-3-yl)pyrimidine-2,4- diamine 70

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(4-isopropylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine 71

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 72

N2-(4-(tert-butyl)pyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine

TABLE 1-12 73

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-isopropylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 74

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(4-propylpyridin-2-yl)pyrimidine- 2,4-diamine 75

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(piperidin-1-yl)-N2-(4-propylpyridin-2-yl)pyrimidine-2,4-diamine 76

N2-(6-(allyloxy)pyridin-3-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 77

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl) pyrimidine-2,4-diamine 78

N2-(6-(difluoromethoxy)pyridin-3-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine

TABLE 1-13 79

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-methylpyridin-3-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 80

N2-(6-cyclobutoxypyridin-3-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 81

N2-(6-(cyclohexyloxy)pyridin-3- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine 82

N4-(imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin- 3-yl)pyrimidine-2,4-diamine 83

N4-(imidazo[1,2-a]pyridin-7-yl)- N6,N6-dimethyl-N2-(6-methylpyridin-3-yl)pyrimidine- 2,4,6-triamine 84

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6,N6-dimethylpyrimidine- 2,4,6-triamine

TABLE 1-14 85

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-methylpyridin-3-yl)pyrimidine-2,4,6-triamine 86

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-methoxypyrimidine-2,4- diamine 87

N2-(5,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 88

N2-(5,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 89

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-6- morpholinopyrimidine- 2,4-diamine 90

N4-(imidazo[1,2-a]pyridin-7- yl)-6-morpholino-N2-(6-phenoxypyridin-3-yl)pyrimidine- 2,4-diamine

TABLE 1-15 91

N2-(6-(benzyloxy)pyridin-3-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 92

6-(azepan-1-yl)-N2-(4-ethylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4- diamine 93

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(4-methoxypyridin-2-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 94

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 95

N2-(6-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine 96

N2-(6-cyclopropylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine

TABLE 1-16 97

(S)-N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(3-methylpiperazin-1- yl)pyrimidine-2,4-diamine 98

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(4-methylpiperidin-1-yl)pyrimidine- 2,4-diamine 99

6-(4,4-dimethylpiperidin-1-yl)- N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 100

(R)-tert-butyl 4-(2-((4-ethylpyridin- 2-yl)amino)-6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin- 4-yl)-2-methylpiperazine-1- carboxylate101

(S)-6-(3,4-dimethylpiperazin-1- yl)-N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine

TABLE 1-17 102

(R)-N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(3-methylpiperazin-1- yl)pyrimidine-2,4-diamine 103

(S)-tert-butyl 4-(2-((4-ethylpyridin- 2-yl)amino)-6-(imidazo[1,2-a]pyridin- 7-ylamino)pyrimidin-4- yl)-2-methylpiperazine-1-carboxylate 104

(R)-6-(3,4-dimethylpiperazin-1-yl)- N2-(4-ethylpyridin-2yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 105

N4-(imidazo[1,2-a]pyridin-7-yl)- 6-(piperidin-1-yl)-N2-(6-propylpyridin-2-yl)pyrimidine-2,4- diamine 106

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine-2,4- diamine

TABLE 1-18 107

N2-(6-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 108

N4-(imidazo[1,2-a]pyridin-7-yl)- 6-morpholino-N2-(6-propylpyridin-2-yl)pyrimidine- 2,4-diamine 109

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine 110

N2-(6-cyclopropylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine-2,4- diamine 111

1-(2-((4-ethylpyridin-2-yl)amino)- 6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)piperidin-4-ol 112

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(4-morpholinopiperidin-1- yl)pyrimidine-2,4-diamine

TABLE 1-19 113

6-([1,4′-bipiperidin]-1′-yl)-N2- (4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 114

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(4-methoxypiperidin-1-yl)pyrimidine- 2,4-diamine 115

1-(2-((4-ethylpyridin-2-yl)amino)- 6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)azetidin-3-ol 116

(R)-1-(2-((4-ethylpyridin-2- yl)amino)-6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)pyrrolidin-3-ol 117

(S)-1-(2-((4-ethylpyridin-2- yl)amino)-6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)pyrrolidin-3-ol

TABLE 1-20 118

6-(azetidin-1-yl)-N2-(4-ethylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4- diamine 119

(1-(2-((4-ethylpyridin-2-yl)amino)- 6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)piperidin-4-yl)methanol 120

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(1,4,7-trioxa-10-azacyclododecan- 10-yl)pyrimidine-2,4- diamine 121

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isopropylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 122

N2-(6-(tert-butyl)pyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine

TABLE 1-21 123

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isopropylpyridin-2-yl)-6-morpholinopyrimidine-2,4- diamine formate 124

N2-(6-(tert-butyl)pyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-morpholinopyrimidine- 2,4-diamine 125

(R)-6-(3-(dimethylamino)pyrrolidin- 1-yl)-N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 126

(S)-6-(3-(dimethylamino)pyrrolidin- 1-yl)-N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 127

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(4-(pyrrolidin-1-yl)piperidin-1- yl)pyrimidine-2,4-diamine

TABLE 1-22 128

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-methoxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine- 2,4-diamine 129

6-(4-(dimethylamino)piperidin- 1-yl)-N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 130

1-(2-((4,6-dimethylpyridin-2- yl)amino)-6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin-4- yl)piperidin-4-ol 131

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(4-methoxypiperidin-1- yl)pyrimidine-2,4-diamine 132

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(4-morpholinopiperidin-1- yl)pyrimidine-2,4-diamine

TABLE 1-23 133

6-([1,4′-bipiperidin]-1′-yl)-N2- (4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 134

6-(4-(dimethylamino)piperidin- 1-yl)-N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 135

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl)pyrimidine- 2,4-diamine 136

1-(2-((4,6-dimethylpyridin-2- yl)amino)-6-(imidazo[1,2-a]pyridin-7-ylamino)pyrimidin- 4-yl)pyrrolidin-3-ol 137

6-(3-(dimethylamino)pyrrolidin- 1-yl)-N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2- a]pyridin-7-yl)pyrimidine- 2,4-diamine

TABLE 1-24 138

6-(3,3-difluoropyrrolidin-1-yl)- N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 139

6-(2,5-dihydro-1H-pyrrol-1-yl)- N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 140

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(3-methoxypyrrolidin-1- yl)pyrimidine-2,4-diamine 141

N2-(4-cyclopropyl-6-methylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1- yl)pyrimidine-2,4-diamine 142

N2-(4,6-dimethylpyridin-2-yl)- 6-(3,3-dimethylpyrrolidin-1-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine

TABLE 1-25 143

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-methoxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine- 2,4-diamine 144

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-methoxypyridin-2-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 145

N2-(4-ethoxypyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 146

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(3-methylpyrrolidin-1- yl)pyrimidine-2,4-diamine 147

N2-(4,6-dimethylpyridin-2-yl)- 6-(3,4-dimethylpyrrolidin-1-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4- diamine formate

TABLE 1-26 148

6-([1,3′-bipyrrolidin]-1′-yl)-N2- (4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 149

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(3-morpholinopyrrolidin-1- yl)pyrimidine-2,4-diamine 150

N2-(6-ethoxypyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 151

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-propoxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 152

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-[6-(2-methoxyethoxy)pyridin-2-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine

TABLE 1-27 153

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isopropoxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine- 2,4-diamine 154

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-[6-(2-morpholinoethoxy)pyridin-2-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine 155

N2-{6-[2-(dimethylamino)ethoxy] pyridin-2-yl}-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin- 1-yl)pyrimidine-2,4-diamine 156

N2-{6-[2-(tert-butoxy)ethoxy] pyridin-2-yl}-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine 157

2-[(6-{[4-(imidazo[1,2-a]pyridin- 7-ylamino)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]amino}pyridin- 2-yl)oxy]ethanol

TABLE 1-28 158

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-isobutoxypyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 159

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-[6-(2-methoxyethyl)pyridin-2-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine 160

N2-[6-(2-ethoxyethyl)pyridin-2- yl]-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine 161

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isobutylpyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 162

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-neopentylpyridin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine- 2,4-diamine

TABLE 1-29 163

N4-(imidazo[1,2-a]pyridin-7- yl)-6-(pyrrolidin-1-yl)-N2-{6-[2-(pyrrolidin-1-yl)ethyl]pyridin- 2-yl}pyrimidine-2,4-diamine triformate164

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-[6-(propoxymethyl)pyridin-2-yl]-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine 165

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4- diamine 166

6-(azetidin-1-yl)-N2-(4,6- dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine- 2,4-diamine 167

6-(azetidin-1-yl)-N2-(6-butyl pyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4- diamine

TABLE 1-30 168

N2-(6-butylpyridin-2-yl)-6-(3,3- dimethylpyrrolidin-1-yl)-N4-(imidazo[l,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 169

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(8-oxa-2-azaspiro[4.5]decan-2-yl) pyrimidine-2,4-diamine 170

6-(3,3-dimethylpyrrolidin-1-yl)- N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 171

N2-[6-(ethoxymethyl)pyridin-2- yl]-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine 172

N2-{6-[2-(dimethylamino)ethyl] pyridin-2-yl}-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin- 1-yl)pyrimidine-2,4-diamine

TABLE 1-31 173

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(2-azaspiro[4.4]nonan-2-yl) pyrimidine-2,4-diamine 174

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(2-azaspiro[4.4]nonan-2- yl)pyrimidine-2,4-diamine 175

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(8-oxa-2-azaspiro[4.5]decan- 2-yl)pyrimidine-2,4-diamine 176

N2-(4,6-dimethylpyridin-2-yl)- 6-[(3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-N4- (imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4-diamine 177

6-(3,3-dimethylazetidin-1-yl)- N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine

TABLE 1-32 178

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)pyrimidine-2,4-diamine 179

N2-(6-butylpyridin-2-yl)-6- ((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-N4-(imidazo [1,2-a]pyridin-7-yl)pyrimidine- 2,4-diamine180

N2-(6-butylpyridin-2-yl)-6-(3,3- dimethylazetidin-1-yl)-N4-(imidazo[1,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 181

N2-(6-butylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyrimidine-2,4-diamine 182

6-(4,4-dimethylpiperidin-1-yl)- N2-(4,6-dimethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridine-7- yl)pyrimidine-2,4-diamine

TABLE 1-33 183

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(4-methylpiperidin-1-yl) pyrimidine-2,4-diamine 184

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-(3-methylpiperidin-1-yl) pyrimidine-2,4-diamine 185

(S)-N2-(4,6-dimethylpyridin-2- yl)-6-(3-fluoropyrrolidin-1-yl)-N4-(imidazo[1,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 186

(R)-N2-(4,6-dimethylpyridin-2- yl)-6-(3-fluoropyrrolidin-1-yl)-N4-(imidazo[1,2-a]pyridin-7-yl) pyrimidine-2,4-diamine 187

N2-(6-butyl-4-methylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine

TABLE 1-34 188

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-isobutyl-4-methylpyridin-2-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 189

N2-(6-ethyl-4-methylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 190

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(4-methoxy-6-methylpyridin-2-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 191

N2-(6-(fluoromethyl)-4- methoxypyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1- yl)pyrimidine-2,4-diamine 192

(6-{[4-(imidazo[1,2-a]pyridin-7- ylamino)-6-(piperidin-1-yl)pyrimidin-2-yl]amino} pyridin-2-yl)methanol

TABLE 1-35 193

N2-(4,6-dimethylpyridin-2-yl)- 6-[trans-3,4-dimethylpyrrolidin-1-yl]-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 194

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-6-[(4aR,7aS)-tetrahydro-2H- [1,4]dioxino[2,3-c]pyrrol-6(3H)-yl]pyrimidine-2,4-diamine 195

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6-phenylpyrimidine-2,4,6- triamine 196

N4-benzyl-N2-(4,6-dimethylpyridin- 2-yl)-N6-(imidazo[1,2-a]pyridin-7-yl)pyrimidine-2,4,6- triamine 197

N2-(6-butyl-4-methoxypyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine

TABLE 1-36 198

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6-(piperidin-1-yl)pyrimidine- 2,4,6-triamine 199

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6-morpholinopyrimidine- 2,4,6-triamine 200

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6-(1H-pyrrol-1-yl)pyrimidine- 2,4,6-triamine 201

N2-(6-butyl-4-ethylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 202

N2-(5-fluoro-6-methylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine

TABLE 1-37 203

N2-(5-chloro-6-methylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 204

N2-(5-fluoro-4-methylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 205

N2-(4-chloro-6-methylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 206

N2-(4,6-dimethylpyridin-2-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N6-(pyrrolidin-1-yl)pyrimidine- 2,4,6-triamine 207

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(4-methoxypyridin-2-yl)-6-(2-azaspiro[4.4]nonan-2-yl) pyrimidine-2,4-diamine

TABLE 1-38 208

N2-(4-ethylpyridin-2-yl)-N4- (imidazo[1,2-a]pyridin-7-yl)-6-(2-azaspiro[4.4]nonan-2-yl) pyrimidine-2,4-diamine 209

6-(3,3-dimethylpyrrolidin-1-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(4-methoxypyridin-2-yl) pyrimidine-2,4-diamine 210

N2-(6-chloro-4-methylpyridin- 2-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(piperidin-1-yl) pyrimidine-2,4-diamine 211

N4-(imidazo[1,2-a]pyridin-7- yl)-N2-(6-isobutylpyridin-2-yl)-6-(piperidin-1-yl)pyrimidine- 2,4-diamine 212

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-isobutyl-4-methylpyridin-2-yl)-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine

TABLE 1-39 213

6-(3,3-dimethylpyrrolidin-1-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(6-isobutyl-4-methylpyridin- 2-yl)pyrimidine-2,4-diamine 214

N2-(6-ethyl-4-methylpyridin-2- yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine 215

6-(3,3-dimethylpyrrolidin-1-yl)- N2-(6-ethyl-4-methylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin- 7-yl)pyrimidine-2,4-diamine 216

6-(3,3-dimethylpyrrolidin-1-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(6-isobutylpyridin-2-yl) pyrimidine-2,4-diamine 217

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(6-isobutylpyridin-2-yl)-6-(2-azaspiro[4.4]nonan-2-yl) pyrimidine-2,4-diamine

TABLE 1-40 218

6-(trans-3,4-dimethylpyrrolidin- 1-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(6-isobutyl pyridin- 2-yl)pyrimidine-2,4-diamine 219

6-(trans-3,4-dimethylpyrrolidin- 1-yl)-N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(4-methoxypyridine- 2-yl)pyrimidine-2,4-diamine 220

6-(trans-3,4-dimethylpyrrolidin- 1-yl)-N2-(4-ethylpyridin-2-yl)-N4-(imidazo[1,2-a]pyridin-7- yl)pyrimidine-2,4-diamine 221

N4-(imidazo[1,2-a]pyridin-7-yl)- N2-(4-methoxy-6-methylpyridin-2-yl)-6-(pyrrolidin-1-yl) pyrimidine-2,4-diamine 222

6-(3,3-dimethylpyrrolidin-1-yl)- N4-(imidazo[1,2-a]pyridin-7-yl)-N2-(4-methoxy-6-methylpyridin- 2-yl)pyrimidine-2,4- diamine carbonate

TABLE 2-1 LCMS Example m/z No. ¹H-NMR δ (ppm) [M + H]⁺ 1 (DMSO-d₆) δ9.17 (s, 1H), 8.96 (s, 1H), 8.48-8.39 (m, 419.2 1H), 8.34 (d, J = 7.3Hz, 1H), 8.15-8.05 (m, 1H), 8.03 (dd, J = 2.9, 8.8 Hz, 1H), 7.72 (s,1H), 7.39 (s, 1H), 6.99 (dd, J = 2.0, 7.3 Hz, 1H), 6.75-6.70 (m, 1H),5.55 (s, 1H), 3.82 (s, 3H), 3.75-3.65 (m, 4H), 3.50-3.49 (m, 4H). 2(CDCl₃) δ 8.01 (dd, J = 7.3, 0.7 Hz, 1H), 7.97-7.92 (m, 417.0 1H),7.92-7.90 (m, 1H), 7.57-7.54 (m, 1H), 7.50-7.47 (m, 2H), 7.11-7.06 (m,1H), 6.92 (dd, J = 7.3, 2.1 Hz, 1H), 6.60-6.57 (m, 1H), 5.65 (s, 1H),3.81-3.75 (m, 4H), 3.60-3.53 (m, 4H), 2.40-2.35 (m, 3H), 2.29-2.26 (m,3H). 3 (DMSO-d₆) δ 14.85 (s, 1H), 11.02 (s, 1H), 389.1 9.33-9.26 (m,2H), 9.02-8.96 (m, 2H), 8.75-8.69 (m, 1H), 8.60-8.55 (m, 1H), 8.17-8.12(m, 1H), 8.05-8.00 (m, 1H), 7.46-7.39 (m, 1H), 7.17-7.11 (m, 2H), 6.35(s, 1H), 3.79-3.71 (m, 4H), 3.71-3.62 (m, 4H). 4 (DMSO-d₆) δ 9.24 (br.s, 1H), 9.22 (br. s, 1H), 389.3 8.90-8.80 (m, 1H), 8.36 (d, J = 7.3 Hz,1H), 8.18-8.09 (m, 3H), 7.74 (s, 1H), 7.42 (s, 1H), 7.28 (dd, J = 4.7,8.1 Hz, 1H), 7.10-6.98 (m, 1H), 5.61 (s, 1H), 3.71-3.69 (m, 4H),3.48-3.47 (m, 4H). 5 (DMSO-d₆) δ 9.24 (s, 1H), 8.47 (dd, J = 1.5, 7.8Hz, 419.3 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.00-7.95 (m, 1H), 7.79-7.73(m, 2H), 7.55 (s, 1H), 7.41 (s, 1H), 7.00-6.95 (m, 2H), 5.62 (s, 1H),3.97 (s, 3H), 3.73-3.67 (m, 4H), 3.55-3.40 (m, 4H). 6 (DMSO-d₆) δ 9.53(s, 1H), 9.29 (s, 1H), 8.75-8.62 (m, 407.3 1H), 8.42-8.35 (m, 1H),8.25-8.15 (m, 1H), 8.07 (d, J = 2.5 Hz, 1H), 8.05-8.00 (m, 1H), 7.75 (s,1H), 7.41 (d, J = 1.5 Hz, 1H), 7.01 (dd, J = 2.0, 7.3 Hz, 1H), 5.65 (s,1H), 3.72-3.70 (m, 4H), 3.49-3.47 (m, 4H). 8 (DMSO-d₆) δ 9.42 (s, 1H),9.29 (s, 1H), 9.13-9.11 (m, 390.3 2H), 8.71 (s, 1H), 8.42-8.35 (m, 1H),8.10-8.02 (m, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 6.99 (dd, J = 2.0, 7.3Hz, 1H), 5.65 (s, 1H), 3.71-3.70 (m, 4H), 3.48-3.47 (m, 4H).

TABLE 2-2 9 (DMSO-d₆) δ 9.14 (br. s, 1H), 8.62 (s, 1H), 403.2 8.40-8.30(m, 1H), 8.25 (d, J = 7.3 Hz, 1H), 8.08-7.98 (m, 1H), 7.67-7.63 (m, 2H),7.36 (d, J = 0.9 Hz, 1H), 7.11 (dd, J = 4.9, 7.3 Hz, 1H), 7.05-6.95 (m,1H), 5.53 (s, 1H), 3.66-3.64 (m, 4H), 3.40-3.37 (m, 4H), 2.22 (s, 3H).10 (DMSO-d₆) δ 9.27 (s, 1H), 9.07 (s, 1H), 403.2 8.40-8.30 (m, 1H),8.06-7.98 (m, 2H), 7.74 (s, 1H), 7.65-7.55 (m, 1H), 7.41 (s, 1H),7.24-7.14 (m, 1H), 6.85-6.75 (m, 1H), 5.63 (s, 1H), 3.71-3.64 (m, 4H),3.48-3.40 (m, 4H), 2.39 (s, 3H). 11 (DMSO-d₆) δ 9.23 (br. s, 1H), 8.71(br. s, 1H), 407.3 8.42-8.38 (m, 1H), 8.36-8.30 (m, 1H), 8.05-7.95 (m,1H), 7.90-7.80 (m, 1H), 7.65-7.75 (m, 1H), 7.45-7.35 (m, 1H), 7.31-7.29(m, 1H), 7.05-6.95 (m, 1H), 5.60 (s, 1H), 3.69-3.65 (m, 4H), 3.44-3.41(m, 4H). 12 (DMSO-d₆) δ 9.27 (br. s, 1H), 9.23 (br. s, 1H), 407.48.54-8.48 (m, 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.32-8.22 (m, 1H),8.15-8.02 (m, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 7.09 (dd, J = 3.4, 8.8Hz, 1H), 6.98 (dd, J = 2.0, 7.3 Hz, 1H), 5.60 (s, 1H), 3.74-3.69 (m,4H), 3.47-3.46 (m, 4H). 13 (DMSO-d₆) δ 9.55 (br. s, 1H), 9.38 (br. s,1H), 407.2 8.44-8.39 (m, 1H), 8.35-8.25 (m, 1H), 8.25-8.18 (m, 1H),8.18-8.10 (m, 1H), 7.85-7.75 (m, 1H), 7.72-7.60 (m, 1H), 7.56-7.45 (m,1H), 7.35-7.20 (m, 1H), 5.69 (s, 1H), 3.81-3.65 (m, 4H), 3.52-3.41 (m,4H). 14 (DMSO-d₆) δ 9.68 (s, 1H), 9.30 (s, 1H), 407.2 8.40-8.35 (m, 1H),8.11-8.07 (m, 2H), 7.88-7.82 (m, 1H), 7.74 (s, 1H), 7.41 (d, J = 1.0 Hz,1H), 7.18 (dd, J = 2.0, 7.3 Hz, 1H), 6.63 (dd, J = 2.5, 7.8 Hz, 1H),5.66 (s, 1H), 3.72-3.70 (m, 4H), 3.49-3.47 (m, 4H). 15 (DMSO-d₆) δ 9.16(s, 1H), 8.92 (s, 1H), 447.3 8.36-8.33 (m, 2H), 8.14-8.02 (m, 1H), 8.01(dd, J = 2.7, 9.1 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 1.0 Hz, 1H), 7.03(dd, J = 2.0, 7.3 Hz, 1H), 6.72-6.65 (m, 1H), 5.56 (s, 1H), 5.17 (dt, J= 6.1, 12.2 Hz, 1H), 3.70-3.67 (m, 4H), 3.46-3.44 (m, 4H), 1.27 (d, J =5.9 Hz, 6H).

TABLE 2-3 16 (DMSO-d₆) δ 9.58 (s, 1H), 9.38-9.29 (m, 2H), 390.4 8.85 (d,J = 4.4 Hz, 2H), 8.38-8.30 (m, 1H), 7.70 (s, 1H), 7.43 (s, 1H),7.12-7.04 (m, 1H), 7.04-6.95 (m, 1H), 5.68 (s, 1H), 3.75-3.65 (m, 4H),3.48-3.38 (m, 4H). 17 (DMSO-d₆) δ 9.33 (s, 1H), 9.01 (s, 1H), 403.28.45-8.35 (m, 1H), 8.13-8.10 (m, 2H), 8.01 (s, 1H), 7.76 (s, 1H), 7.43(s, 1H), 7.18-7.10 (m, 1H), 6.85-6.75 (m, 1H), 5.64 (s, 1H), 3.72-3.70(m, 4H), 3.50-3.49 (m, 4H), 2.26 (s, 3H). 18 (DMSO-d₆) δ 9.23 (s, 1H),9.05 (s, 1H), 403.3 8.40-8.30 (m, 1H), 8.13-8.04 (m, 3H), 7.78-7.72 (m,1H), 7.52 (dd, J = 2.2, 8.6 Hz, 1H), 7.40 (s, 1H), 7.20-7.10 (m, 1H),5.61 (s, 1H), 3.70-3.69 (m, 4H), 3.48-3.47 (m, 4H), 2.23 (s, 3H). 19(DMSO-d₆) δ 9.37 (br. s, 1H), 9.30 (br. s, 1H), 417.2 8.48-8.42 (m, 1H),8.42-8.36 (m, 1H), 8.20-8.10 (m, (M - H) 1H), 7.96-7.91 (m, 1H),7.87-7.82 (m, 1H), 7.81-7.75 (m, 1H), 7.50-7.44 (m, 1H), 7.10 (dd, J =1.5, 7.3 Hz, 1H), 5.64 (s, 1H), 3.75-3.70 (m, 7H), 3.50-3.49 (m, 4H). 20(DMSO-d₆) δ 9.19 (s, 1H), 9.12 (s, 1H), 407.3 8.32-8.27 (m, 2H),8.17-8.10 (m, 1H), 7.73-7.68 (m, 2H), 7.38 (s, 1H), 7.28-7.20 (m, 1H),6.96 (dd, J = 2.0, 7.3 Hz, 1H), 5.58 (s, 1H), 3.49-3.47 (m, 4H),3.71-3.64 (m, 4H). 21 (DMSO-d₆) δ 9.68 (br. s, 1H), 9.38 (br. s, 1H),407.2 8.38-8.31 (m, 2H), 8.08-8.00 (m, 2H), 7.85-7.70 (m, 1H), 7.50-7.35(m, 1H), 7.25-7.10 (m, 1H), 6.95-6.75 (m, 1H), 5.69 (s, 1H), 3.75-3.61(m, 4H), 3.50-3.46 (m, 4H). 22 (DMSO-d₆) δ 10.03 (s, 1H), 9.50 (br. s,1H), 8.78 (s, 390.3 1H), 8.52-8.45 (m, 1H), 8.45-8.38 (m, 1H), 8.19 (s,1H), 8.16-8.12 (m, 1H), 7.80 (s, 1H), 7.49 (s, 1H), 7.30-7.20 (m, 1H),5.73 (s, 1H), 3.72-3.50 (m, 8H). 23 (DMSO-d₆) δ 9.20 (s, 1H), 8.98 (s,1H), 419.2 8.37-8.30 (m, 1H), 8.20-8.12 (m, 1H), 7.93-7.88 (m, 1H),7.78-7.73 (m, 1H), 7.73-7.70 (m, 1H), 7.38 (d, J = 1.2 Hz, 1H),7.13-7.07 (m, 1H), 6.98 (dd, J = 2.0, 7.2 Hz, 1H), 5.57 (s, 1H), 3.92(s, 3H), 3.69-3.67 (m, 4H), 3.45-3.44 (m, 4H).

TABLE 2-4 24 (DMSO-d₆) δ 11.22 (s, 1H), 9.16 (br. s, 1H), 403.1 8.60(br. s, 1H), 8.40-8.30 (m, 1H), 7.79-7.65 (m, 4H), (M - H) 7.39 (s, 1H),7.06-7.01 (m, 1H), 6.38-6.30 (m, 1H), 5.51 (s, 1H), 3.72-3.66 (m, 4H),3.42-3.38 (m, 4H). 25 (DMSO-d₆) δ 9.23 (s, 1H), 8.99 (s, 1H), 416.18.40-8.32 (m, 1H), 8.16-8.11 (m, 1H), 8.11-8.05 (m, 1H), 8.05-8.00 (m,1H), 7.73 (s, 1H), 7.39 (s, 1H), 7.07 (dd, J = 2.0, 7.3 Hz, 1H),6.82-6.72 (m, 1H), 5.63 (s, 1H), 3.53-3.51 (m, 4H), 2.41-2.36 (m, 4H),2.26 (s, 3H), 2.22 (s, 3H). 26 (DMSO-d₆) δ 9.14 (s, 1H), 8.96 (s, 1H),399.2 8.38-8.30 (m, 1H), 8.11-8.05 (m, 3H), 7.72 (s, 1H), (M - H)7.58-7.50 (m, 1H), 7.39 (br. s, 1H), 7.18-7.10 (m, 1H), 5.61 (s, 1H),3.54-3.48 (m, 4H), 2.23 (s, 3H), 1.64-1.54 (m, 6H). 27 (DMSO-d₆) δ 9.19(br. s, 1H), 9.03 (br. s, 1H), 416.1 8.40-8.30 (m, 1H), 8.20-7.95 (m,3H), 7.78-7.70 (m, 1H), 7.58-7.48 (m, 1H), 7.45-7.35 (m, 1H), 7.18-7.10(m, 1H), 5.61 (s, 1H), 3.55-3.45 (m, 4H), 2.39-2.32 (m, 4H), 2.27 (s,3H), 2.20 (s, 3H). 28 (DMSO-d₆) δ 9.15 (s, 1H), 8.97 (s, 1H), 401.28.38-8.30 (m, 1H), 8.03-7.99 (m, 2H), 7.78-7.70 (m, 1H), 7.65-7.52 (m,1H), 7.39 (s, 1H), 7.16 (dd, J = 2.0, 7.3 Hz, 1H), 6.85-6.75 (m, 1H),5.62 (s, 1H), 3.58-3.53 (m, 4H), 2.39 (s, 3H), 1.64-1.55 (m, 6H). 29(DMSO-d₆) δ 9.56 (s, 1H), 9.45 (s, 1H), 362.2 8.42-8.33 (m, 1H),8.15-8.08 (m, 1H), 8.06-7.98 (m, 1H), 7.80-7.72 (m, 1H), 7.68-7.58 (m,1H), 7.46-7.38 (m, 1H), 7.17 (dd, J = 2.0, 7.3 Hz, 1H), 6.88-6.80 (m,1H), 5.67 (s, 1H), 4.33 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H), 1.34 (t, J =7.1 Hz, 3H). 30 (DMSO-d₆) δ 9.22 (s, 1H), 8.88 (s, 1H), 430.1 8.38-8.31(m, 1H), 8.06-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.71 (m, 1H),7.42-7.37 (m, 1H), 7.16-7.09 (m, 1H), 6.69-6.62 (m, 1H), 5.62 (s, 1H),3.56-3.48 (m, 4H), 2.44-2.37 (m, 4H), 2.34 (s, 3H), 2.26-2.20 (m, 6H).

TABLE 2-5 31 (DMSO-d₆) δ 9.19 (s, 1H), 8.89 (s, 1H), 430.2 8.37-8.31 (m,1H), 8.07-8.00 (m, 1H), 7.92-7.87 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36(m, 1H), 7.17-7.10 (m, 1H), 6.67-6.62 (m, 1H), 5.60 (s, 1H), 4.17-4.09(m, 1H), 4.03-3.98 (m, 1H), 2.98 (d, J = 11.2 Hz, 2H), 2.89-2.78 (m,1H), 2.76-2.68 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.05 (d, J = 6.2 Hz,3H). 32 (DMSO-d₆) δ 9.34 (s, 1H), 8.79 (s, 1H), 415.2 8.42-8.36 (m, 1H),8.13-8.08 (m, 1H), 7.94-7.87 (m, 1H), 7.82-7.77 (m, 1H), 7.51-7.46 (m,1H), 7.25 (dd, J = 7.3, 2.2 Hz, 1H), 6.67-6.62 (m, 1H), 5.65 (s, 1H),3.59-3.52 (m, 4H), 2.35 (s, 3H), 2.23 (s, 3H), 1.70-1.51 (m, 6H). 33(DMSO-d₆) δ 9.46 (s, 1H), 9.35 (s, 1H), 376.2 8.41-8.35 (m, 1H),8.11-8.05 (m, 1H), 7.91-7.86 (m, 1H), 7.79-7.74 (m, 1H), 7.46-7.40 (m,1H), 7.16 (dd, J = 7.3, 2.2 Hz, 1H), 6.71-6.66 (m, 1H), 5.68 (s, 1H),4.35 (q, J = 7.0 Hz, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 1.35 (t, J = 7.0Hz, 3H). 34 (DMSO-d₆) δ 9.18 (br. s, 1H), 8.91 (s, 1H), 401.2 8.38-8.31(m, 1H), 8.12-8.05 (m, 3H), 7.73 (s, 1H), 7.39 (s, 1H), 7.14-7.05 (m,1H), 6.80-6.75 (m, 1H), 5.63 (s, 1H), 3.62-3.56 (m, 4H), 2.25 (s, 3H),1.70-1.56 (m, 6H). 35 (DMSO-d₆) δ 9.21 (br. s, 1H), 9.00 (br. s, 1H),430.2 8.42-8.35 (m, 1H), 8.15-8.11 (m, 1H), 8.11-8.06 (m, 1H), 8.06-8.00(m, 1H), 7.76-7.70 (m, 1H), 7.43-7.37 (m, 1H), 7.15-7.05 (m, 1H)6.82-6.75 (m, 1H), 5.63 (s, 1H), 4.02-3.96 (m, 2H), 3.17-3.16 (m, 1H),3.03-2.99 (m, 2H), 2.91-2.80 (m, 2H), 2.27 (s, 3H), 2.22 (s, 3H), 1.07(d, J = 5.9 Hz, 3H). 36 (DMSO-d₆) δ 9.50-9.40 (m, 2H), 8.42-8.32 (m,362.2 1H), 8.18-8.14 (m, 2H), 8.05-8.00 (m, 1H), 7.75 (s, 1H), 7.41 (s,1H), 7.09 (dd, J = 2.0, 7.3 Hz, 1H), 6.85-6.79 (m, 1H), 5.68 (s, 1H),4.35 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

TABLE 2-6 37 (DMSO-d₆) δ 9.18 (s, 1H), 8.99 (s, 1H), 430.2 8.38-8.31 (m,1H), 8.14-8.09 (m, 1H), 8.09-8.02 (m, 2H), 7.75-7.70 (m, 1H), 7.53 (dd,J = 8.7, 2.4 Hz, 1H), 7.40 (s, 1H), 7.14 (dd, J = 7.5, 2.1 Hz, 1H), 5.62(s, 1H), 4.00 (dd, J = 25.9, 12.9 Hz, 2H), 3.07-2.96 (m, 1H), 2.80 (dd,J = 8.6, 5.7 Hz, 1H), 2.67-2.59 (m, 1H), 2.23 (d, J = 8.3 Hz, 6H),2.19-2.02 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H). 38 (DMSO-d₆) δ 9.55-9.47(br. s, 1H), 9.47-9.39 (br. 362.2 s, 1H), 8.45-8.32 (m, 1H), 8.14 (d, J= 10.3 Hz, 2H), 8.06 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.57-7.55 (m,1H), 7.42 (s, 1H), 7.20-7.10 (m, 1H), 5.66 (s, 1H), 4.33 (q, J = 6.8 Hz,2H), 2.24 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 39 (DMSO-d₆) δ 9.19 (s,1H), 9.00 (s, 1H), 414.3 8.38-8.30 (m, 1H), 8.07-8.01 (m, 1H), 8.01-7.95(m, 1H), (M − 7.72 (s, 1H), 7.65-7.55 (m, 1H), 7.39 (d, J = 1.5 Hz, H)1H), 7.16 (dd, J = 2.2, 7.6 Hz, 1H), 6.85-6.75 (m, 1H), 5.62 (s, 1H),3.55-3.48 (m, 4H), 2.42-2.38 (m, 7H), 2.22 (s, 3H). 40 (DMSO-d₆) δ 9.19(s, 1H), 8.99 (s, 1H), 430.2 8.39-8.30 (m, 1H), 8.08-8.01 (m, 1H),8.01-7.94 (m, 1H), 7.73 (s, 1H), 7.65-7.55 (m, 1H), 7.40 (s, 1H),7.17-7.16 (m, 1H), 6.85-6.75 (m, 1H), 5.62 (s, 1H), 4.05-3.94 (m, 2H),3.09-2.95 (m, 1H), 2.82-2.80 (m, 1H), 2.66-2.59 (m, 1H), 2.39 (s, 3H),2.21 (s, 3H), 2.16-2.06 (m, 2H), 1.05 (d, J = 6.4 Hz, 3H). 41 (DMSO-d₆)δ 9.98 (s, 1H), 9.90 (s, 1H), 384.1 8.51-8.47 (m, 1H), 8.47-8.39 (m,1H), 8.28-8.20 (m, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.87-7.82 (m, 1H),7.82-7.78 (m, 1H), 7.75-7.65 (m, 1H), 7.46 (s, 1H), 7.27-7.20 (m, 1H),7.17 (s, 1H), 6.90 (d, J = 7.3 Hz, 1H), 6.48 (s, 1H), 2.44 (s, 3H). 42(DMSO-d₆) δ 9.95 (s, 1H), 9.91 (s, 1H), 384.2 8.50-8.46 (m, 1H),8.46-8.41 (m, 1H), 8.33-8.26 (m, 1H), 8.23 (d, J = 4.9 Hz, 11), 7.95 (s,1H), 7.87-7.82 (m, 1H), 7.82-7.78 (m, 1H), 7.46 (s, 1H), 7.21-7.16 (m,1H), 7.16-7.10 (m, 1H), 6.91-6.84 (m, 1H), 6.49 (s, 1H), 2.30 (s, 3H).

TABLE 2-7 43 (DMSO-d₆) δ 9.96 (s, 1H), 9.90 (s, 1H), 384.1 8.52-8.46 (m,1H), 8.46-8.44 (m, 1H), 8.33-8.27 (m, 1H), 8.21-8.20 (m, 1H), 8.04 (d, J= 8.3 Hz, 1H), 7.88-7.78 (m, 2H), 7.63 (dd, J = 2.2, 8.6 Hz, 1H),7.50-7.43 (m, 1H), 7.21-7.17 (m, 2H), 6.47 (s, 1H), 2.27 (s, 3H). 44(DMSO-d₆) δ 9.06 (br. s, 1H), 8.66 (br. s, 1H), 333.2 8.41-8.30 (m, 1H),8.25 (d, J = 8.3 Hz, 1H), 8.08 (s, 1H), 7.95 (br. s, 1H), 7.72 (br. s,1H), 7.49 (dd, J = 2.0, 8.8 Hz, 1H), 7.40 (br. s, 1H), 7.13 (d, J = 6.8Hz, 1H), 6.33 (br. s, 2H), 5.49 (s, 1H), 2.23 (s, 3H). 45 (DMSO-d₆) δ9.19 (s, 1H), 8.89 (s, 1H), 444.2 8.37-8.30 (m, 1H), 8.06-8.01 (m, 1H),7.91-7.86 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J =7.4, 2.2 Hz, 1H), 6.67-6.62 (m, 1H), 5.62 (s, 1H), 4.12-3.94 (m, 2H),3.08-2.97 (m, 1H), 2.86-2.77 (m, 1H), 2.67-2.59 (m, 1H), 2.35 (s, 3H),2.24 (s, 3H), 2.22 (s, 3H), 2.08-2.02 (m, 2H), 1.05 (dd, J = 8.1, 6.4Hz, 3H). 46 (DMSO-d₆) δ 9.95 (s, 1H), 9.80 (s, 1H), 398.1 8.48-8.46 (m,1H), 8.45-8.41 (m, 1H), 8.21-8.16 (m, 1H), 7.86-7.78 (m, 3H), 7.48-7.43(m, 1H), 7.21-7.14 (m, 2H), 6.77-6.72 (m, 1H), 6.50 (s, 1H), 2.39 (s,3H), 2.28 (s, 3H). 47 (DMSO-d₆) δ 10.05 (s, 1H), 9.31 (s, 1H), 457.18.60-8.57 (m, 1H), 8.56-8.53 (m, 1H), 8.37-8.29 (m, 1H), 8.18-8.12 (m,1H), 7.77-7.71 (m, 1H), 7.43-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.16 (dd,J = 7.4, 2.2 Hz, 1H), 5.68 (s, 1H), 3.75-3.68 (m, 4H), 3.53-3.46 (m,4H). 48 (DMSO-d₆) δ 9.25 (s, 1H), 9.18 (s, 1H), 419.0 8.38-8.29 (m, 1H),8.12-8.04 (m, 2H), 7.83 (d, J = 2.3 Hz, 1H), 7.76-7.70 (m, 1H),7.42-7.37 (m, 1H), 7.20-7.13 (m, 1H), 6.53 (dd, J = 5.7, 2.4 Hz, 1H),5.64 (s, 1H), 3.74 (s, 3H), 3.73-3.67 (m, 4H), 3.53-3.46 (m, 4H).

TABLE 2-8 49 (DMSO-d₆) δ 10.30 (s, 1H), 9.40 (s, 1H), 434.0 9.08-9.03(m, 1H), 8.65-8.59 (m, 1H), 8.39-8.33 (m, 1H), 8.23-8.18 (m, 1H),7.78-7.73 (m, 1H), 7.65-7.58 (m, 1H), 7.45-7.40 (m, 1H), 7.18 (dd, J =7.4, 2.2 Hz, 1H), 5.71 (s, 1H), 3.78-3.70 (m, 4H), 3.59-3.51 (m, 4H). 50(DMSO-d₆) δ 9.08 (s, 1H), 8.57 (s, 1H), 333.2 8.39-8.30 (m, 1H),8.20-8.11 (m, 1H), 8.11-8.05 (m, 1H), 8.20-7.92 (m, 1H), 7.72 (s, 1H),7.38 (s, 1H), 7.12-7.02 (m, 1H), 6.70-6.60 (m, 1H), 6.34 (br. s, 2H),5.49 (s, 1H), 2.27 (s, 3H). 51 (DMSO-d₆) δ 9.06 (s, 1H), 8.58 (s, 1H),431.2 8.37-8.30 (m, 1H), 8.15-7.95 (m, 2H), 7.74-7.69 (m, 1H), 7.61-7.53(m, 1H), 7.41-7.35 (m, 1H), 6.95 (dd, J = 7.4, 2.2 Hz, 1H), 6.41-6.33(m, 1H), 5.52 (s, 1H), 3.85 (q, J = 7.1 Hz, 2H), 3.54-3.46 (m, 4H),1.71-1.46 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H). 52 (500 MHz, DMSO-d₆) δ9.10 (s, 1H), 8.62 (s, 1H), 460.4 8.37-8.31 (m, 1H), 8.17-7.93 (m, 2H),7.74-7.70 (m, 1H), 7.61-7.54 (m, 1H), 7.41-7.37 (m, 1H), 6.99-6.93 (m,1H), 6.40-6.34 (m, 1H), 5.53 (s, 1H), 3.96-3.92 (m, 2H), 3.86 (q, J =7.2 Hz, 2H), 3.03-2.94 (m, 1H), 2.83-2.77 (m, 1H), 2.63-2.57 (m, 1H),2.22 (s, 3H), 2.16-2.09 (m, 1H), 2.07-2.03 (m, 1H), 1.17-1.13 (m, 3H),1.04 (d, J = 6.2 Hz, 3H). 53 (DMSO-d₆) δ 9.36 (s, 1H), 9.16 (s, 1H),461.2 8.42-8.30 (m, 1H), 8.15-8.03 (m, 1H), 7.78 (s, 1H), 7.66-7.54 (m,1H), 7.46 (s, 1H), 7.33-7.21 (m, 1H), 5.61 (s, 1H), 3.72-3.71 (m, 4H),3.50-3.48 (m, 4H), 2.35 (d, J = 2.8 Hz, 3H), 2.07-2.03 (m, 1H),1.01-1.00 (m, 2H), 0.71-0.61 (m, 2H).

TABLE 2-9 54 (500 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.64 (s, 1H), 333.0 8.33(dd, J = 7.4, 0.8 Hz, 1H), 8.23-8.15 (m, 1H), 7.95-7.90 (m, 1H),7.74-7.70 (m, 1H), 7.59-7.51 (m, 1H), 7.41-7.36 (m, 1H), 7.18-7.12 (m,1H), 6.81-6.75 (m, 1H), 6.35 (s, 2H), 5.49 (s, 1H), 2.38 (s, 3H). 55(500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.60 (s, 1H), 445.3 8.37-8.32 (m,1H), 8.23-7.98 (m, 2H), 7.75-7.71 (m, 1H), 7.60 (dd, J = 9.7, 2.9 Hz,1H), 7.43-7.39 (m, 1H), 7.03-6.98 (m, 1H), 6.41-6.35 (m, 1H), 5.53 (s,1H), 5.14-5.07 (m, 1H), 3.55-3.48 (m, 4H), 1.69-1.47 (m, 6H), 1.25 (d, J= 6.7 Hz, 6H). 56 (DMSO-d₆) δ 9.15-9.07 (m, 1H), 8.68-8.57 (m, 474.71H), 8.38-8.28 (m, 1H), 8.05-7.94 (m, 1H), 7.76-7.68 (m, 1H), 7.66-7.57(m, 1H), 7.44-7.33 (m, 1H), 7.02-6.90 (m, 1H), 6.43-6.33 (m, 1H), 5.53(s, 1H), 5.16-5.00 (m, 1H), 4.05-3.86 (m, 2H), 3.03-2.91 (m, 1H),2.85-2.75 (m, 1H), 2.65-2.56 (m, 1H), 2.21 (s, 3H), 2.19-1.94 (m, 2H),1.32-1.18 (m, 6H), 1.04 (d, J = 6.1 Hz, 3H). 57 (DMSO-d₆) δ 9.33 (s,1H), 8.96 (s, 1H), 406.4 8.39-8.32 (m, 1H), 8.01-7.96 (m, 2H), 7.77-7.71(m, 1H), 7.68-7.60 (m, 1H), 7.43-7.38 (m, 1H), 6.99-6.92 (m, 1H),6.44-6.36 (m, 1H), 5.56 (s, 1H), 5.10-5.05 (m, 1H), 4.30 (q, J = 7.0 Hz,2H), 1.30 (t, J = 7.0 Hz, 3H), 1.28-1.19 (m, 6H). 58 (500 MHz, DMSO-d₆)δ 9.06 (s, 1H), 8.45 (s, 1H), 347.2 8.36-8.31 (m, 1H), 8.02-7.98 (m,1H), 7.95-7.90 (m, 1H), 7.74-7.70 (m, 1H), 7.40-7.35 (m, 1H), 7.10 (dd,J = 7.4, 2.2 Hz, 1H), 6.64-6.60 (m, 1H), 6.34 (s, 2H), 5.48 (s, 1H),2.33 (s, 3H), 2.23 (s, 3H). 59 (Methanol-d₄) δ 8.33-8.26 (m, 1H), 460.18.19-8.14 (m, 1H), 8.13-8.08 (m, 1H), 7.76-7.67 (m, 2H), 7.48 (s, 1H),7.18-7.11 (m, 1H), 6.60-6.53 (m, 1H), 5.59 (s, 1H), 5.29-5.19 (m, 1H),3.66-3.59 (m, 4H), 2.62-2.54 (m, 4H), 2.39 (s, 3H), 1.36 (d, J = 6.7 Hz,6H).

TABLE 2-10 60 (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 9.12 (s, 1H), 403.18.76-8.72 (m, 1H), 8.36 (dd, J = 7.3, 0.9 Hz, 1H), 8.11 (s, 1H), 8.02(dd, J = 8.4, 2.7 Hz, 1H), 7.75-7.71 (m, 1H), 7.42-7.38 (m, 1H), 7.14(d, J = 8.4 Hz, 1H), 7.01 (dd, J = 7.4, 2.2 Hz, 1H), 5.58 (s, 1H),3.73-3.67 (m, 4H), 3.49-3.43 (m, 4H), 2.39 (s, 3H). 61 (DMSO-d₆) δ 9.17(s, 1H), 8.94 (s, 1H), 476.1 8.40-8.37 (m, 1H), 8.36-8.32 (m, 1H),8.12-8.05 (m, 1H), 8.02 (dd, J = 8.9, 2.7 Hz, 1H), 7.72 (s, 1H), 7.39(s, 1H), 6.99 (dd, J = 7.4, 2.0 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.56(s, 1H), 4.28 (t, J = 6.0 Hz, 2H), 3.73-3.65 (m, 4H), 3.48-3.41 (m, 4H),2.60 (t, J = 5.9 Hz, 2H), 2.20 (s, 6H). 62 (DMSO-d₆) δ 9.13 (s, 1H),8.91 (s, 1H), 461.3 8.39-8.35 (m, 1H), 8.35-8.28 (m, 1H), 8.08-8.03 (m,1H), 7.99 (dd, J = 8.9, 2.7 Hz, 1H), 7.72-7.67 (m, 1H), 7.40-7.34 (m,1H), 6.97 (dd, J = 7.4, 2.2 Hz, 1H), 6.76-6.68 (m, 1H), 5.53 (s, 1H),4.18 (t, J = 6.6 Hz, 2H), 3.71-3.63 (m, 4H), 3.46-3.37 (m, 4H),1.72-1.60 (m, 2H), 1.47-1.33 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 63(DMSO-d₆) δ 9.14 (s, 1H), 8.90 (s, 1H), 461.4 8.36-8.32 (m, 1H),8.32-8.30 (m, 1H), 8.09-7.99 (m, 2H), 7.74-7.69 (m, 1H), 7.42-7.36 (m,1H), 7.00 (dd, J = 7.4, 2.1 Hz, 1H), 6.68-6.61 (m, 1H), 5.55 (s, 1H),3.72-3.65 (m, 4H), 3.48-3.41 (m, 4H), 1.50 (s, 9H). 64 (DMSO-d₆) δ 9.14(s, 1H), 8.91 (s, 1H), 461.3 8.42-8.36 (m, 1H), 8.36-8.29 (m, 1H), 8.07(s, 1H), 8.01 (dd, J = 8.9, 2.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.42-7.37(m, 1H), 7.00 (dd, J = 7.4, 2.2 Hz, 1H), 6.79-6.72 (m, 1H), 5.55 (s,1H), 3.98 (d, J = 6.7 Hz, 2H), 3.73-3.65 (m, 4H), 3.48-3.41 (m, 4H),2.06-1.97 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H). 65 (DMSO-d₆) δ 9.14 (s,1H), 8.92 (s, 1H), 475.3 8.44-8.37 (m, 1H), 8.34 (dd, J = 7.5, 0.8 Hz,1H), 8.08 (s, 1H), 8.01 (dd, J = 8.9, 2.8 Hz, 1H), 7.74-7.69 (m, 1H),7.42-7.36 (m, 1H), 7.00 (dd, J = 7.4, 2.2 Hz, 1H), 6.77 (d, J = 8.9 Hz,1H), 5.55 (s, 1H), 3.90 (s, 2H), 3.73-3.66 (m, 4H), 3.48-3.41 (m, 4H),0.99 (s, 9H).

TABLE 2-11 66 (DMSO-d₆) δ 9.16 (s, 1H), 8.94 (s, 1H), 463.4 8.43-8.36(m, 1H), 8.36-8.30 (m, 1H), 8.13-8.06 (m, 1H), 8.03 (dd, J = 8.9, 2.7Hz, 1H), 7.74-7.69 (m, 1H), 7.42-7.37 (m, 1H), 6.99 (dd, J = 7.3, 2.1Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.55 (s, 1H), 4.33 (t, J = 4.7 Hz,2H), 3.74-3.67 (m, 4H), 3.65 (t, J = 4.8 Hz, 2H), 3.48-3.39 (m, 4H),3.30 (s, 3H). 67 (DMSO-d₆) δ 9.24 (s, 1H), 9.18 (s, 1H), 8.33 (dd, J =7.7, 445.1 1.0 Hz, 1H), 8.19-8.17 (m, 1H), 8.17 (dd, J = 1.8, 0.7 Hz,1H), 8.13-8.11 (m, 1H), 7.77-7.69 (m, 1H), 7.43-7.35 (m, 1H), 7.17 (dd,J = 7.4, 2.2 Hz, 1H), 6.97 (dd, J = 5.3, 1.8 Hz, 1H), 5.62 (s, 1H),3.74-3.67 (m, 4H), 3.57-3.49 (m, 4H), 1.23 (s, 9H). 68 (DMSO-d₆) δ 9.26(s, 1H), 9.10 (s, 1H), 8.35 (dd, J = 7.3, 417.1 0.8 Hz, 1H), 8.15 (dd, J= 5.1, 0.7 Hz, 1H), 8.07 (s, 2H), 7.76-7.71 (m, 1H), 7.40 (d, J = 1.2Hz, 1H), 7.12 (dd, J = 7.4, 2.2 Hz, 1H), 6.80 (dd, J = 5.1, 1.5 Hz, 1H),5.63 (s, 1H), 3.75-3.65 (m, 4H), 3.58-3.43 (m, 4H), 2.58 (q, J = 7.6 Hz,2H), 1.10 (t, J = 7.6 Hz, 3H). 69 (DMSO-d₆) δ 9.16 (s, 1H), 8.95 (s,1H), 447.3 8.43-8.37 (m, 1H), 8.37-8.31 (m, 1H), 8.09 (s, 1H), 8.01 (dd,J = 8.9, 2.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.42-7.36 (m, 1H), 6.99 (dd, J= 7.5, 2.2 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 5.55 (s, 1H), 4.15 (t, J =6.7 Hz, 2H), 3.73-3.66 (m, 4H), 3.48-3.41 (m, 4H), 1.72 (h, J = 7.2 Hz,2H), 0.97 (t, J = 7.4 Hz, 3H). 70 (DMSO-d₆) δ 9.25 (s, 1H), 9.16 (s,1H), 8.34 (dd, J = 7.3, 431.0 0.8 Hz, 1H), 8.16 (dd, J = 5.2, 0.7 Hz,1H), 8.09 (dd, J = 2.0, 0.9 Hz, 1H), 8.08-8.06 (m, 1H), 7.77-7.68 (m,1H), 7.41-7.36 (m, 1H), 7.15 (dd, J = 7.4, 2.2 Hz, 1H), 6.83 (dd, J =5.3, 1.5 Hz, 1H), 5.63 (s, 1H), 3.71 (dd, J = 5.9, 3.8 Hz, 4H),3.56-3.46 (m, 4H), 2.89-2.74 (m, 1H), 1.16 (d, J = 6.9 Hz, 6H). 71(DMSO-d₆) δ 9.16 (s, 1H), 9.01 (s, 1H), 8.34 (dd, J = 7.4, 415.1 0.8 Hz,1H), 8.14 (dd, J = 5.1, 0.7 Hz, 1H), 8.10 (dd, J = 1.6, 0.8 Hz, 1H),8.08-8.05 (m, 1H), 7.76-7.69 (m, 1H), 7.43-7.35 (m, 1H), 7.13 (dd, J =7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.63 (s, 1H),3.61-3.51 (m, 4H), 2.58 (q, J = 7.6 Hz, 2H), 1.70-1.51 (m, 6H), 1.13 (t,J = 7.6 Hz, 3H).

TABLE 2-12 72 (DMSO-d₆) δ 9.15 (s, 1H), 9.08 (s, 1H), 8.32 (dd, J = 7.4,443.0 0.8 Hz, 1H), 8.23 (dd, J = 1.8, 0.8 Hz, 1H), 8.17 (dd, J = 5.3,0.7 Hz, 1H), 8.13-8.07 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.34 (m, 1H),7.18 (dd, J = 7.4, 2.2 Hz, 1H), 6.96 (dd, J = 5.4, 1.8 Hz, 1H), 5.62 (s,1H), 3.64-3.53 (m, 4H), 1.71-1.51 (m, 6H), 1.25 (s, 9H). 73 (DMSO-d₆) δ9.15 (s, 1H), 9.06 (s, 1H), 8.33 (dd, J = 7.4, 429.0 0.8 Hz, 1H), 8.15(dd, J = 5.1, 0.7 Hz, 1H), 8.14-8.12 (m, 1H), 8.11-8.04 (m, 1H),7.76-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.16 (dd, J = 7.4, 2.2 Hz, 1H),6.82 (dd, J = 5.2, 1.5 Hz, 1H), 5.63 (s, 1H), 3.63-3.52 (m, 4H),2.89-2.76 (m, 1H), 1.72-1.51 (m, 6H), 1.18 (d, J = 6.9 Hz, 6H). 74(DMSO-d₆) δ 9.26 (s, 1H), 9.09 (s, 1H), 8.35 (dd, J = 7.4, 431.2 0.8 Hz,1H), 8.14 (dd, J = 5.1, 0.7 Hz, 1H), 8.07 (dd, J = 1.9, 0.9 Hz, 1H),8.05 (dd, J = 1.6, 0.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.44-7.37 (m, 1H),7.11 (dd, J = 7.4, 2.2 Hz, 1H), 6.78 (dd, J = 5.1, 1.5 Hz, 1H), 5.62 (s,1H), 3.76-3.66 (m, 4H), 3.56-3.45 (m, 4H), 2.55-2.51 (m, 2H), 1.60-1.46(m, 2H), 0.82 (t, J = 7.3 Hz, 3H). 75 (DMSO-d₆) δ 9.16 (s, 1H), 9.01 (s,1H), 8.34 (dd, J = 7.4, 429.2 0.8 Hz, 1H), 8.13 (dd, J = 5.1, 0.7 Hz,1H), 8.10 (dd, J = 1.7, 0.8 Hz, 1H), 8.08-8.06 (m, 1H), 7.77-7.69 (m,1H), 7.44-7.35 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz, 1H), 6.77 (dd, J =5.1, 1.5 Hz, 1H), 5.63 (s, 1H), 3.61-3.52 (m, 4H), 2.55-2.52 (m, 2H),1.73-1.48 (m, 8H), 0.83 (t, J = 7.3 Hz, 3H). 76 (DMSO-d₆) δ 9.15 (s,1H), 8.69 (s, 1H), 8.34 (d, J = 7.3 Hz, 445.3 1H), 8.12-8.07 (m, 1H),8.05-8.00 (m, 1H), 7.75-7.70 (m, 1H), 7.59 (dd, J = 9.6, 2.9 Hz, 1H),7.39 (d, J = 1.2 Hz, 1H), 6.95 (dd, J = 7.5, 2.2 Hz, 1H), 6.42 (d, J =9.6 Hz, 1H), 5.94-5.80 (m, 1H), 5.51 (s, 1H), 5.17-5.09 (m, 1H),5.04-4.95 (m, 1H), 4.51 (d, J = 5.8 Hz, 2H), 3.72-3.64 (m, 4H),3.46-3.38 (m, 4H). 77 (DMSO-d₆) δ 9.18 (s, 1H), 9.07 (s, 1H), 487.38.50-8.44 (m, 1H), 8.35 (d, J = 7.3 Hz, 1H), 8.11 (dd, J = 8.9, 2.7 Hz,1H), 8.09-8.04 (m, 1H), 7.75-7.70 (m, 1H), 7.42-7.36 (m, 1H), 6.98 (dd,J = 7.3, 2.2 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.57 (s, 1H), 4.95 (q, J= 9.2 Hz, 2H), 3.70 (t, J = 5.1 Hz, 4H), 3.49-3.42 (m, 4H).

TABLE 2-13 78 (DMSO-d₆) δ 9.22 (s, 2H), 8.58-8.52 (m, 1H), 455.38.39-8.32 (m, 1H), 8.22 (dd, J = 8.8, 2.8 Hz, 1H), 8.10-8.05 (m, 1H),7.75-7.70 (m, 1H), 7.42-7.37 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.97(dd, J = 7.4, 2.2 Hz, 1H), 5.60 (s, 1H), 3.74-3.67 (m, 4H), 3.50-3.42(m, 4H), 3.36 (s, 1H). 79 (DMSO-d₆) δ 9.11 (s, 1H), 9.05 (s, 1H), 401.38.80-8.73 (m, 1H), 8.35 (dd, J = 7.3, 0.8 Hz, 1H), 8.12-8.06 (m, 1H),8.03 (dd, J = 8.4, 2.7 Hz, 1H), 7.76-7.69 (m, 1H), 7.42-7.36 (m, 1H),7.18-7.07 (m, 1H), 7.00 (dd, J = 7.4, 2.2 Hz, 1H), 5.58 (s, 1H),3.57-3.48 (m, 4H), 2.39 (s, 3H), 1.71-1.49 (m, 6H). 80 (DMSO-d₆) δ 9.15(s, 1H), 8.92 (s, 1H), 8.34 (dd, J = 5.0, 459.2 2.4 Hz, 2H), 8.09-7.99(m, 2H), 7.74-7.69 (m, 1H), 7.42-7.36 (m, 1H), 7.03-6.95 (m, 1H), 6.71(d, J = 8.9 Hz, 1H), 5.55 (s, 1H), 5.08 (p, J = 7.4 Hz, 1H), 3.73-3.65(m, 4H), 3.48-3.40 (m, 4H), 2.44-2.32 (m, 2H), 2.10-1.95 (m, 2H),1.83-1.56 (m, 2H). 81 (DMSO-d₆) δ 9.16 (s, 1H), 8.92 (s, 1H), 487.58.36-8.35 (m, 1H), 8.35-8.33 (m, 1H), 8.10-8.05 (m, 1H), 8.01 (dd, J =8.9, 2.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.42-7.36 (m, 1H), 6.99 (dd, J =7.4, 2.2 Hz, 1H), 6.70 (d, J = 8.8 Hz, H), 5.55 (s, 1H), 4.96-4.85 (m,1H), 3.73-3.65 (m, 4H), 3.48-3.40 (m, 4H), 2.00-1.91 (m, 2H), 1.77-1.69(m, 2H), 1.63-1.13 (m, 6H). 82 (DMSO-d₆) δ 9.16 (s, 1H), 8.94 (s, 1H),489.4 8.40-8.36 (m, 1H), 8.36-8.32 (m, 1H), 8.11-8.05 (m, 1H), 8.02 (dd,J = 8.9, 2.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.41-7.36 (m, 1H), 6.97 (dd, J= 7.4, 2.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.55 (s, 1H), 5.15-5.06(m, 1H), 3.91-3.81 (m, 21), 3.73-3.65 (m, 4H), 3.54-3.41 (m, 61),2.04-1.96 (m, 21), 1.68-1.54 (m, 21). 83 (DMSO-d₆) δ 9.12 (s, 1H), 9.05(s, 1H), 360.9 8.83-8.75 (m, 1H), 8.34 (dd, J = 7.4, 0.8 Hz, 1H),8.14-8.09 (m, 2H), 7.75-7.69 (m, 1H), 7.44-7.36 (m, 1H), 7.18-7.08 (m,1H), 7.02 (dd, J = 7.4, 2.2 Hz, 1H), 5.46 (s, 1H), 3.03 (s, 6H), 2.39(s, 3H).

TABLE 2-14 84 (DMSO-d₆) δ 9.18 (s, 1H), 8.79 (s, 1H), 8.33 (dd, J = 7.4,375.1 0.8 Hz, 1H), 8.06-8.01 (m, 1H), 8.01-7.96 (m, 1H), 7.76-7.68 (m,1H), 7.42-7.36 (m, 1H), 7.17 (dd, J = 7.4, 2.2 Hz, 1H), 6.67-6.61 (m,1H), 5.50 (s, 1H), 3.05 (s, 6H), 2.34 (s, 3H), 2.24 (s, 3H). 85(DMSO-d₆) δ 8.99 (s, 1H), 8.91 (s, 1H), 8.74 (dd, J = 2.7, 332.9 0.7 Hz,1H), 8.34 (dd, J = 7.4, 0.8 Hz, 1H), 8.20 (dd, J = 8.4, 2.6 Hz, 1H),8.00-7.93 (m, 1H), 7.77-7.68 (m, 1H), 7.42-7.34 (m, 1H), 7.13-7.07 (m,1H), 7.02 (dd, J = 7.4, 2.2 Hz, 1H), 6.26 (s, 2H), 5.45 (s, 1H), 2.39(s, 3H). 86 (DMSO-d₆) δ 9.46 (s, 1H), 9.42 (s, 1H), 8.37 (dd, J = 7.4,361.9 0.8 Hz, 1H), 8.12-8.04 (m, 1H), 7.95-7.87 (m, 1H), 7.79-7.71 (m,1H), 7.46-7.37 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H), 6.74-6.64 (m,1H), 5.70 (s, 1H), 3.89 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H). 87(DMSO-d₆) δ 9.22 (s, 1H), 8.91 (s, 1H), 8.34 (dd, J = 7.4, 417.2 0.8 Hz,1H), 8.04-8.00 (m, 1H), 7.94-7.87 (m, 1H), 7.75-7.71 (m, 1H), 7.46-7.41(m, 1H), 7.41-7.38 (m, 1H), 7.19 (dd, J = 7.4, 2.2 Hz, 1H), 5.60 (s,1H), 3.74-3.66 (m, 4H), 3.51-3.44 (m, 4H), 2.35 (s, 3H), 2.19 (s, 3H).88 (DMSO-d₆) δ 9.13 (s, 1H), 8.79 (s, 1H), 415.0 8.35-8.32 (m, 1H),8.03-7.99 (m, 1H), 7.95-7.88 (m, 1H), 7.75-7.71 (m, 1H), 7.47-7.40 (m,1H), 7.40-7.37 (m, 1H), 7.18 (dd, J = 7.4, 2.2 Hz, 1H), 5.60 (s, 1H),3.59-3.46 (m, 4H), 2.35 (s, 3H), 2.19 (s, 3H), 1.69-1.48 (m, 6H). 89(DMSO-d₆) δ 9.16 (s, 1H), 8.92 (s, 1H), 502.4 8.38-8.30 (m, 2H), 8.07(s, 1H), 8.01 (dd, J = 8.8, 2.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.41-7.34(m, 1H), 6.98 (dd, J = 7.4, 2.1 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 5.55(s, 1H), 4.95-4.84 (m, 1.H), 3.73-3.65 (m, 4H), 3.48-3.37 (m, 4H),2.68-2.58 (m, 2H), 2.22-2.09 (m, 5H), 2.04-1.87 (m, 2H), 1.64 (dtd, J =12.9, 9.1, 3.7 Hz, 2H).

TABLE 2-15 90 (DMSO-d₆) δ 9.19 (s, 1H), 9.14 (s, 1H), 8.46 (d, J = 2.8Hz, 481.4 1H), 8.38-8.31 (m, H), 8.20 (dd, J = 8.8, 2.8 Hz, 1H),8.12-8.07 (m, 1H), 7.72 (s, 1H), 7.44-7.35 (m, 3H), 7.20-7.13 (m, 1H),7.13-7.07 (m, 2H), 6.98 (dd, J = 8.1, 2.6 Hz, 2H), 5.58 (s, 1H),3.73-3.66 (m, 4H), 3.49-3.41 (m, 4H). 91 (DMSO-d₆) δ 9.18 (s, 1H), 8.97(s, 1H), 495.4 8.45-8.40 (m, 1H), 8.39-8.31 (m, 1H), 8.10-8.02 (m, 2H),7.75-7.70 (m, 1H), 7.49-7.27 (m, 6H), 7.01 (dd, J = 7.3, 2.1 Hz, 1H),6.84 (d, J = 8.8 Hz, 1H), 5.56 (s, 1H), 5.31 (s, 2H), 3.73-3.66 (m, 4H),3.49-3.41 (m, 4H). 92 (DMSO-d₆) δ 9.14 (s, 1H), 8.97 (s, 1H), 8.33 (dd,J = 7.4, 429.1 0.8 Hz, 1H), 8.22-8.18 (m, 1H), 8.15-8.12 (m, 1H),8.10-8.06 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.17 (dd, J =7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.52 (s, 1H),3.90-3.42 (in, 4H), 2.58 (q, J = 7.6 Hz, 2H), 1.81-1.72 (m, 4H),1.58-1.47 (m, 4H), 1.15 (t, J = 7.6 Hz, 3H). 93 (DMSO-d₆) δ 9.16 (s,1H), 9.08 (s, 1H), 8.33 (dd, J = 7.3, 417.1 0.8 Hz, 1H), 8.09-8.03 (m,2H), 7.91-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.17 (dd,J = 7.4, 2.2 Hz, 1H), 6.52 (dd, J = 5.8, 2.4 Hz, 1H), 5.64 (s, 1H), 3.76(s, 3H), 3.60-3.53 (m, 4H), 1.70-1.50 (m, 6H). 94 (DMSO-d₆) δ 9.16 (s,1H), 8.91 (s, 1H), 8.33 (dd, J = 7.4, 401.2 0.8 Hz, 1H), 8.30-8.28 (m,1H), 8.16-8.10 (m, 1H), 8.09-8.04 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36(m, 1H), 7.18 (dd, J = 7.5, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H),5.37 (s, 1H), 3.47-3.42 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 2.00-1.92 (m,4H), 1.16 (t, J = 7.6 Hz, 3H).

TABLE 2-16 95 (500 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.88 (s, 1H), 415.28.34 (dd, J = 7.4, 0.8 Hz, 1H), 8.06-8.04 (m, 1H), 8.03-8.00 (m, 1H),7.75-7.70 (m, 1H), 7.65-7.58 (m, 1H), 7.42-7.36 (m, 1H), 7.15 (dd, J =7.4, 2.2 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 5.63 (s, 1H), 3.57-3.51 (m,4H), 2.66 (q, J = 7.6 Hz, 2H), 1.69-1.60 (m, 2H), 1.60-1.51 (m, 4H),1.24 (t, J = 7.6 Hz, 3H). 96 (500 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.66 (s,1H), 427.2 8.37-8.32 (m, 1H), 8.07-8.03 (m, 1H), 7.95 (dd, J = 8.4, 0.9Hz, 1H), 7.75-7.70 (m, 1H), 7.58-7.51 (m, 1H), 7.39 (d, J = 1.3 Hz, 1H),7.10 (dd, J = 7.4, 2.1 Hz, 1H), 6.83 (dd, J = 7.4, 0.9 Hz, 1H), 5.62 (s,1H), 3.57-3.50 (m, 4H), 2.04-1.95 (m, 1H), 1.68-1.51 (m, 6H), 0.98-0.86(m, 4H). 97 (DMSO-d₆) δ 9.17 (s, 1H), 9.04 (s, 1H), 8.34 (dd, J = 7.4,430.1 0.8 Hz, 1H), 8.14 (dd, J = 5.1, 0.7 Hz, 1H), 8.11-8.08 (m, 1H),8.08-8.06 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J =7.4, 2.2 Hz, 1H), 6.80 (dd, J = 5.1, 1.5 Hz, 1H), 5.61 (s, 1H),4.15-4.07 (m, 1H), 4.05-3.97 (m, 1H), 2.95 (dt, J = 11.7, 2.4 Hz, 1H),2.81 (td, J = 11.9, 3.0 Hz, 1H), 2.74-2.63 (m, 2H), 2.59 (q, J = 7.6 Hz,2H), 2.48-2.34 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 6.2 Hz,3H). 98 (DMSO-d₆) δ 9.15 (s, 1H), 8.99 (s, 1H), 8.34 (dd, J = 7.4, 429.10.8 Hz, 1H), 8.14 (dd, J = 5.0, 0.7 Hz, 1H), 8.11-8.09 (m, 1H),8.07-8.05 (m, 1H), 7.75-7.70 (m, 1H), 7.39 (d, J = 1.2 Hz, 1H), 7.13(dd, J = 7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.64 (s, 1H),4.28-4.20 (m, 2H), 2.95-2.83 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H),1.72-1.60 (m, 3H), 1.19-1.03 (m, 5H), 0.93 (d, J = 6.0 Hz, 3H). 99(DMSO-d₆) δ 9.16 (s, 1H), 9.02 (s, 1H), 443.1 8.37-8.29 (m, 1H), 8.14(dd, J = 5.1, 0.7 Hz, 1H), 8.12-8.09 (m, 1H), 8.09-8.06 (m, 1H),7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H),6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.64 (s, 1H), 3.61-3.53 (m, 4H), 2.58(q, J = 7.6 Hz, 2H), 1.42-1.34 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H), 0.99(s, 6H).

TABLE 2-17 100 (DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 8.34 (dd, J =7.4, 530.1 0.8 Hz, 1H), 8.15 (dd, J = 5.0, 0.7 Hz, 1H), 8.10-8.04 (m,2H), 7.76-7.70 (m, 1H), 7.42-7.37 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz,1H), 6.81 (dd, J = 5.2, 1.5 Hz, 1H), 5.60 (s, 1H), 4.25-4.16 (m, 1H),4.09-3.96 (m, 2H), 3.85-3.75 (m, 1H), 3.31-3.27 (m, 1H), 3.25-3.14 (m,1H), 3.10-2.98 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.43 (s, 9H),1.17-1.08 (m, 6H). 101 (DMSO-d₆) δ 9.20 (s, 1H), 9.07 (s, 1H), 8.34 (dd,J = 7.4, 444.1 0.8 Hz, 1H), 8.15 (dd, J = 5.0, 0.7 Hz, 1H), 8.11-8.05(m, 2H), 7.76-7.70 (m, 1H), 7.43-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2Hz, 1H), 6.80 (dd, J = 5.1, 1.5 Hz, 1H), 5.63 (s, 1H), 4.04 (d, J = 10.6Hz, 2H), 3.09-2.97 (m, 1H), 2.86-2.77 (m, 1H), 2.65 (dd, J = 12.7, 10.1Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.22 (s, 3H), 2.20-2.10 (m, 1H),2.10-2.01 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.1 Hz, 3H).102 (DMSO-d₆) δ 9.17 (s, 1H), 9.04 (s, 1H), 8.34 (dd, J = 7.4, 430.2 0.8Hz, 1H), 8.16-8.12 (m, 1H), 8.11-8.08 (m, 1H), 8.08-8.06 (m, 1H),7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H),6.80 (dd, J = 5.2, 1.5 Hz, 1H), 5.61 (s, 1H), 4.15-4.05 (m, 1H),4.05-3.97 (m, 1H), 2.99-2.90 (m, 1H), 2.87-2.75 (m, 1H), 2.73-2.63 (m,2H), 2.59 (q, J = 7.6 Hz, 2H), 2.45 (dd, J = 12.3, 10.3 Hz, 1H),2.40-2.30 (m, 1H), 1.14 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 6.2 Hz, 3H).103 (DMSO-d₆) δ 9.24 (s, 1H), 9.06 (s, 1H), 8.34 (dd, J = 7.4, 530.2 0.8Hz, 1H), 8.15 (dd, J = 5.1, 0.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.76-7.70(m, 1H), 7.42-7.37 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H), 6.81 (dd, J= 5.1, 1.5 Hz, 1H), 5.60 (s, 1H), 4.25-4.16 (m, 1H), 4.09-3.96 (m, 2H),3.85-3.75 (m, 1H), 3.31-3.27 (m, 1H), 3.25-3.16 (m, 1H), 3.10-2.98 (m,1H), 2.60 (q, J = 7.6 Hz, 2H), 1.43 (s, 9H), 1.17-1.08 (m, 6H).

TABLE 2-18 104 (DMSO-d₆) δ 9.20 (s, 1H), 9.07 (s, 1H), 8.34 (dd, J =7.4, 444.1 0.8 Hz, 1H), 8.15 (dd, J = 5.0, 0.7 Hz, 1H), 8.10-8.05 (m,2H), 7.76-7.70 (m, 1H), 7.43-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz,1H), 6.80 (dd, J = 5.1, 1.5 Hz, 1H), 5.63 (s, 1H), 4.07-3.97 (m, 2H),3.03 (td, J = 11.8, 3.1 Hz, 1H), 2.86-2.77 (m, 1H), 2.66 (dd, J = 12.7,10.1 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.22 (s, 3H), 2.19-2.11 (m, 1H),2.11-2.01 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.1 Hz, 3H).105 (DMSO-d₆) δ 9.15 (s, 1H), 8.86 (s, 1H), 429.2 8.37-8.30 (m, 1H),8.07-7.98 (m, 2H), 7.73 (s, 1H), 7.65-7.56 (m, 1H), 7.42-7.37 (m, 1H),7.16 (dd, J = 7.3, 2.2 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 5.63 (s, 1H),3.58-3.45 (m, 4H), 2.66-2.57 (m, 2H), 1.77-1.50 (m, 8H), 0.92 (t, J =7.4 Hz, 3H). 106 (DMSO-d₆) δ 9.15 (s, 1H), 8.86 (s, 1H), 8.34 (d, J =443.2 7.3 Hz, 1H), 8.06-8.03 (m, 1H), 8.03-7.99 (m, 1H), 7.72 (s, 1H),7.64-7.55 (m, 1H), 7.42-7.37 (m, 1H), 7.16 (dd, J = 7.5, 2.1 Hz, 1H),6.79 (d, J = 7.3 Hz, 1H), 5.63 (s, 1H), 3.58-3.50 (m, 4H), 2.64 (t, J =7.7 Hz, 2H), 1.72-1.50 (m, 8H), 1.41-1.26 (m, 2H), 0.91 (t, J = 7.3 Hz,3H). 107 (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.00 (s, 1H), 417.18.38-8.32 (m, 1H), 8.09-8.04 (m, 1H), 8.04-7.98 (m, 1H), 7.76-7.72 (m,1H), 7.62 (t, J = 7.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.17 (dd, J = 7.5, 2.2Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 5.62 (s, 1H), 3.74-3.68 (m, 4H),3.51-3.45 (m, 4H), 2.67 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).108 (DMSO-d₆) δ 9.24 (s, 1H), 8.98 (s, 1H), 8.34 (d, J = 431.2 7.3 Hz,1H), 8.08-8.04 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.76-7.71 (m, 1H),7.61 (t, J = 7.9 Hz, 1H), 7.43-7.37 (m, 1H), 7.16 (dd, J = 7.3, 2.2 Hz,1H), 6.80 (d, J = 7.3 Hz, 1H), 5.62 (s, 1H), 3.74-3.67 (m, 4H),3.52-3.44 (m, 4H), 2.62 (t, J = 7.6 Hz, 2H), 1.70 (h, J = 7.4 Hz, 2H),0.92 (t, J = 7.3 Hz, 3H).

TABLE 2-19 109 (DMSO-d₆) δ 9.22 (s, 1H), 8.97 (s, 1H), 445.2 8.36-8.29(m, 1H), 8.07-8.02 (m, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.74-7.69 (m, 1H),7.59 (t, J = 7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.14 (dd, J = 7.5, 2.1 Hz,1H), 6.78 (d, J = 7.3 Hz, 1H), 5.60 (s, 1H), 3.73-3.65 (m, 4H),3.50-3.42 (m, 4H), 2.66-2.58 (m, 2H), 1.71-1.59 (m, 2H), 1.32 (h, J =7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 110 (500 MHz, DMSO-d₆) δ 9.43 (s,1H), 8.78 (s, 1H), 429.1 8.43-8.36 (m, 1H), 8.17-8.11 (m, 1H), 7.93 (d,J = 8.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.52-7.48(m, 1H), 7.26-7.20 (m, 1H), 6.84 (d, J = 7.4 Hz, 1H), 5.64 (s, 1H),3.74-3.68 (m, 4H), 3.51-3.45 (m, 4H), 2.05-1.96 (m, 1H), 0.98-0.86 (m,4H). 111 (DMSO-d₆) δ 9.17 (s, 1H), 9.02 (s, 1H), 8.34 (dd, J = 7.4,431.1 0.8 Hz, 1H), 8.14 (dd, J = 5.0, 0.7 Hz, 1H), 8.11-8.03 (m, 2H),7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H),6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.65 (s, 1H), 4.78-4.73 (m, 1H),4.02-3.92 (m, 2H), 3.81-3.70 (m, 1H), 3.25-3.13 (m, 2H), 2.59 (q, J =7.6 Hz, 2H), 1.86-1.75 (m, 2H), 1.45-1.28 (m, 2H), 1.13 (t, J = 7.6 Hz,3H). 112 (DMSO-d₆) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.34 (dd, J = 7.4,500.4 0.8 Hz, 1H), 8.14 (dd, J = 5.1, 0.7 Hz, 1H), 8.11-8.08 (m, 1H),8.08-8.04 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.12 (dd, J =7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.65 (s, 1H), 4.26 (s,2H), 3.60-3.53 (m, 5H), 2.98-2.85 (m, 2H), 2.59 (q, J = 7.5 Hz, 2H),2.49-2.40 (m, 4H), 1.89-1.81 (m, 2H), 1.46-1.31 (m, 2H), 1.13 (t, J =7.6 Hz, 3H). 113 (DMSO-d₆) δ 9.17 (s, 1H), 9.01 (s, 1H), 8.34 (dd, J =7.3, 498.1 0.8 Hz, 1H), 8.14 (dd, J = 5.0, 0.7 Hz, 1H), 8.11-8.08 (m,1H), 8.08-8.05 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.12 (dd,J = 7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.65 (s, 1H),4.33-4.25 (m, 2H), 2.92-2.81 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H),2.48-2.42 (m, 5H), 1.83-1.74 (m, 2H), 1.53-1.32 (m, 8H), 1.13 (t, J =7.6 Hz, 3H).

TABLE 2-20 114 (DMSO-d₆) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.34 (dd, J =7.4, 445.1 0.8 Hz, 1H), 8.14 (dd, J = 5.2, 0.7 Hz, 1H), 8.11-8.04 (m,2H), 7.77-7.68 (m, 1H), 7.42-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz,1H), 6.83-6.76 (m, 1H), 5.66 (s, 1H), 3.95-3.85 (m, 2H), 3.53-3.40 (m,1H), 3.29 (s, 3H), 3.28-3.22 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H),1.97-1.85 (m, 2H), 1.52-1.38 (m, 2H), 1.13 (t, J = 7.6 Hz, 3H). 115(DMSO-d₆) δ 9.19 (s, 1H), 9.05 (s, 1H), 8.33 (dd, J = 7.4, 403.1 0.8 Hz,1H), 8.26-8.20 (m, 1H), 8.16-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.75-7.70(m, 1H), 7.41-7.36 (m, 1H), 7.15 (dd, J = 7.4, 2.2 Hz, 1H), 6.82-6.76(m, 1H), 5.74 (d, J = 6.3 Hz, 1H), 5.27 (s, 1H), 4.65-4.58 (m, 1H),4.26-4.17 (m, 2H), 3.75 (dd, J = 8.7, 4.5 Hz, 2H), 2.59 (q, J = 7.6 Hz,2H), 1.15 (t, J = 7.6 Hz, 3H). 116 (DMSO-d₆) δ 9.16 (s, 1H), 8.93 (s,1H), 8.33 (dd, J = 7.4, 417.0 0.8 Hz, 1H), 8.31-8.27 (m, 1H), 8.16-8.09(m, 1H), 8.09-8.03 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.18(dd, J = 7.4, 2.2 Hz, 1H), 6.82-6.76 (m, 1H), 5.39-5.34 (m, 1H),5.04-4.98 (m, 1H), 4.43-4.38 (m, 1H), 3.65-3.43 (m, 4H), 2.60 (q, J =7.6 Hz, 2H), 2.11-1.83 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). 117 (DMSO-d₆)δ 9.16 (s, 1H), 8.93 (s, 1H), 8.33 (dd, J = 7.4, 417.1 0.8 Hz, 1H), 8.29(dd, J = 1.7, 0.9 Hz, 1H), 8.16-8.09 (m, 1H), 8.09-8.03 (m, 1H),7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.18 (dd, J = 7.5, 2.2 Hz, 1H),6.79 (dd, J = 5.1, 1.4 Hz, 1H), 5.39-5.34 (m, 1H), 5.04-4.98 (m, 1H),4.43-4.38 (m, 1H), 3.72-3.39 (m, 4H), 2.60 (q, J = 7.6 Hz, 2H),2.13-1.84 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). 118 (DMSO-d₆) δ 9.19 (s,1H), 9.00 (s, 1H), 8.33 (dd, J = 7.4, 387.1 0.8 Hz, 1H), 8.26-8.21 (m,1H), 8.14 (dd, J = 5.1, 0.8 Hz, 1H), 8.10-8.04 (m, 1H), 7.75-7.70 (m,1H), 7.41-7.36 (m, 1H), 7.15 (dd, J = 7.4, 2.2 Hz, 1H), 6.79 (dd, J =5.1, 1.5 Hz, 1H), 5.25 (s, 1H), 4.02 (t, J = 7.4 Hz, 4H), 2.58 (q, J =7.6 Hz, 2H), 2.43-2.33 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H).

TABLE 2-21 119 (DMSO-d₆) δ 9.15 (s, 1H), 9.00 (s, 1H), 8.33 (dd, J =7.4, 445.1 0.8 Hz, 1H), 8.14 (dd, J = 5.0, 0.7 Hz, 1H), 8.12-8.09 (m,1H), 8.08-8.04 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd,J = 7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.64 (s, 1H), 4.49(t, J = 5.3 Hz, 1H), 4.27 (d, J = 12.7 Hz, 2H), 3.31-3.26 (m, 2H),2.96-2.84 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.77-1.62 (m, 3H),1.22-1.07 (m, 5H). 120 (DMSO-d₆) δ 9.15 (s, 1H), 8.95 (s, 1H), 505.38.36-8.29 (m, 1H), 8.17-8.10 (m, 2H), 8.09-8.02 (m, 1H), 7.74-7.69 (m,1H), 7.41-7.36 (m, 1H), 7.15 (dd, J = 7.5, 2.2 Hz, 1H), 6.80 (dd, J =5.1, 1.5 Hz, 1H), 5.59 (s, 1H), 3.90-3.51 (m, 16H), 2.58 (q, J = 7.6 Hz,2H), 1.14 (t, J = 7.6 Hz, 3H). 121 (DMSO-d₆) δ 9.15 (s, 1H), 8.75 (s,1H), 429.4 8.37-8.31 (m, 1H), 8.08-8.04 (m, 1H), 8.04-7.98 (m, 1H),7.75-7.70 (m, 1H), 7.67-7.58 (m, 1H), 7.42-7.37 (m, 1H), 7.13 (dd, J =7.3, 2.1 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 5.63 (s, 1H), 3.58-3.50 (m,4H), 2.99-2.84 (m, 1H), 1.69-1.50 (m, 6H), 1.24 (d, J = 6.9 Hz, 6H). 122(DMSO-d₆) δ 9.16 (s, 1H), 8.60 (s, 1H), 8.35 (d, J = 443.2 7.3 Hz, 1H),8.11-8.03 (m, 1H), 8.03-7.96 (m, 1H), 7.73 (s, 1H), 7.68-7.59 (m, 1H),7.42-7.37 (m, 1H), 7.09 (dd, J = 7.4, 2.2 Hz, 1H), 6.96 (d, J = 7.6 Hz,1H), 5.63 (s, 1H), 3.58-3.51 (m, 4H), 1.69-1.50 (m, 6H), 1.32 (s, 9H).123 (DMSO-d₆) δ 9.29 (s, 1H), 8.89 (s, 1H), 431.3 8.40-8.34 (m, 1H),8.27-8.22 (m, 2H), 8.14-8.08 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H),7.78-7.73 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.15 (d,J = 7.2 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.64 (s, 1H), 3.80-3.59 (m,4H), 3.56-3.45 (m, 4H), 3.00-2.84 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H).

TABLE 2-22 124 (DMSO-d₆) δ 9.27 (s, 1H), 8.72 (s, 1H), 445.2 8.40-8.33(m, 1H), 8.11-8.05 (m, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.76-7.71 (m, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.43-7.38 (m, 1H), 7.11 (dd, J = 7.4, 2.1 Hz,1H), 6.97 (d, J = 7.5 Hz, 1H), 5.63 (s, 1H), 3.75-3.67 (m, 4H),3.52-3.45 (m, 4H), 1.32 (s, 9H). 125 (DMSO-d₆) δ 9.16 (s, 1H), 8.98 (s,1H), 8.32 (dd, J = 7.4, 444.1 0.8 Hz, 1H), 8.31-8.27 (m, 1H), 8.13 (dd,J = 5.1, 0.7 Hz, 1H), 8.09-8.04 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36(m, 1H), 7.19 (dd, J = 7.4, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H),5.37 (s, 1H), 4.03-3.35 (m, 3H), 3.25-3.08 (m, 1H), 2.87-2.69 (m, 1H),2.59 (q, J = 7.6 Hz, 2H), 2.26-2.14 (m, 7H), 1.90-1.75 (m, 1H), 1.16 (t,J = 7.6 Hz, 3H). 126 (DMSO-d₆) δ 9.17 (s, 1H), 8.99 (s, 1H), 8.33 (dd, J= 7.4, 444.0 0.8 Hz, 1H), 8.31-8.27 (m, 1H), 8.16-8.11 (m, 1H),8.10-8.06 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.19 (dd, J =7.5, 2.2 Hz, 1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.37 (s, 1H),3.25-3.10 (m, 2H), 2.88-2.71 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H),2.26-2.13 (m, 7H), 1.92-1.75 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). 127(DMSO-d₆) δ 9.17 (s, 1H), 9.00 (s, 1H), 8.34 (dd, J = 7.4, 484.4 0.8 Hz,1H), 8.14 (dd, J = 5.1, 0.8 Hz, 1H), 8.10-8.08 (m, 1H), 8.07-8.05 (m,1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz,1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.65 (s, 1H), 4.17-4.09 (m, 2H),3.08-2.97 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 2.53-2.51 (m, 4H),2.32-2.20 (m, 1H), 1.95-1.86 (m, 2H), 1.74-1.63 (m, 4H), 1.47-1.33 (m,2H), 1.13 (t, J = 7.6 Hz, 3H). 128 (DMSO-d₆) δ 9.17 (s, 1H), 9.02 (s,1H), 8.32 (dd, J = 7.3, 403.0 0.8 Hz, 1H), 8.13-8.10 (m, 1H), 8.09-8.06(m, 1H), 8.06-8.03 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.23(dd, J = 7.4, 2.2 Hz, 1H), 6.52 (dd, J = 5.7, 2.4 Hz, 1H), 5.38 (s, 1H),3.80 (s, 3H), 3.59-3.39 (m, 4H), 2.00-1.92 (m, 4H).

TABLE 2-23 129 (DMSO-d₆) δ 9.18 (s, 1H), 9.02 (s, 1H), 8.34 (dd, J =7.4, 458.2 0.8 Hz, 1H), 8.14 (dd, J = 5.1, 0.8 Hz, 1H), 8.11-8.08 (m,1H), 8.08-8.06 (m, 1H), 7.75-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.12 (dd,J = 7.4, 2.2 Hz, 1H), 6.80 (dd, J = 5.1, 1.5 Hz, 1H), 5.65 (s, 1H),4.30-4.21 (m, 2H), 2.97-2.85 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H),2.43-2.32 (m, 1H), 2.18 (s, 6H), 1.86-1.78 (m, 2H), 1.43-1.28 (m, 2H),1.13 (t, J = 7.6 Hz, 3H). 130 (DMSO-d₆) δ 9.16 (s, 1H), 8.80 (s, 1H),431.4 8.37-8.30 (m, 1H), 8.04-7.99 (m, 1H), 7.90-7.85 (m, 1H), 7.75-7.70(m, 1H), 7.41-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.1 Hz, 1H), 6.69-6.62(m, 1H), 5.64 (s, 1H), 4.73 (d, J = 4.3 Hz, 1H), 4.01-3.90 (m, 2H),3.80-3.69 (m, 1H), 3.25-3.09 (m, 2H), 2.34 (s, 3H), 2.23 (s, 3H),1.85-1.76 (m, 2H), 1.44-1.30 (m, 2H). 131 (DMSO-d₆) δ 9.19 (s, 1H), 8.82(s, 1H), 445.4 8.38-8.31 (m, 1H), 8.05-8.00 (m, 1H), 7.90-7.85 (m, 1H),7.76-7.71 (m, 1H), 7.42-7.37 (m, 1H), 7.13 (dd, J = 7.3, 2.2 Hz, 1H),6.67-6.62 (m, 1H), 5.65 (s, 1H), 3.94-3.84 (m, 2H), 3.51-3.40 (m, 1H),3.27 (d, J = 16.2 Hz, 5H), 2.34 (s, 3H), 2.23 (s, 3H), 1.97-1.86 (m,2H), 1.44 (dtd, J = 12.8, 8.9, 3.7 Hz, 2H). 132 (DMSO-d₆) δ 9.18 (s,1H), 8.81 (s, 1H), 500.5 8.38-8.31 (m, 1H), 8.05-7.99 (m, 1H), 7.90-7.85(m, 1H), 7.75-7.70 (m, 1H), 7.42-7.37 (m, 1H), 7.13 (dd, J = 7.4, 2.1Hz, 1H), 6.69-6.62 (m, 1H), 5.65 (s, 1H), 4.29-4.20 (m, 2H), 3.60-3.53(m, 4H), 2.96-2.84 (m, 2H), 2.48-2.39 (m, 5H), 2.34 (s, 3H), 2.24 (s,3H), 1.91-1.82 (m, 2H), 1.45-1.30 (m, 2H). 133 (DMSO-d₆) δ 9.17 (s, 1H),8.80 (s, 1H), 8.34 (d, J = 498.5 7.4 Hz, 1H), 8.04-7.99 (m, 1H),7.91-7.86 (m, 1H), 7.75-7.70 (m, 1H), 7.42-7.34 (m, 1H), 7.12 (dd, J =7.4, 2.2 Hz, 1H), 6.67-6.62 (m, 1H), 5.64 (s, 1H), 4.31-4.23 (m, 2H),2.93-2.79 (m, 2H), 2.48-2.41 (m, 5H), 2.34 (s, 3H), 2.24 (s, 3H),1.83-1.75 (m, 2H), 1.52-1.31 (m, 8H).

TABLE 2-24 134 (DMSO-d₆) δ 9.16 (s, 1H), 8.81 (s, 1H), 8.34 (d, J =458.4 7.4 Hz, 1H), 8.04-7.99 (m, 1H), 7.91-7.86 (m, 1H), 7.75-7.70 (m,1H), 7.41-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz, 1H), 6.67-6.62 (m,1H), 5.64 (s, 1H), 4.28-4.19 (m, 2H), 2.96-2.84 (m, 2H), 2.43-2.32 (m,4H), 2.24 (s, 3H), 2.19 (s, 6H), 1.87-1.78 (m, 2H), 1.43-1.28 (m, 2H).135 (DMSO-d₆) δ 9.15 (s, 1H), 8.69 (s, 1H), 8.32 (d, J = 401.2 7.3 Hz,1H), 8.10-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.40-7.35(m, 1H), 7.19 (dd, J = 7.5, 2.2 Hz, 1H), 6.65-6.60 (m, 1H), 5.36 (s,1H), 3.53-3.37 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 2.04-1.86 (m, 4H).136 (DMSO-d₆) δ 9.15 (s, 1H), 8.72 (s, 1H), 417.4 8.36-8.29 (m, 1H),8.10-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.41-7.34 (m,1H), 7.20 (dd, J = 7.4, 2.2 Hz, 1H), 6.66-6.61 (m, 1H), 5.35 (s, 1H),5.03-4.97 (m, 1H), 4.43-4.38 (m, 1H), 4.13-4.04 (m, 1H), 3.68-3.40 (m,3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.09-1.97 (m, 1H), 1.95-1.90 (m, 1H).137 (DMSO-d₆) δ 9.16 (s, 1H), 8.77 (s, 1H), 444.4 8.36-8.29 (m, 1H),8.12-8.06 (m, 1H), 8.06-8.00 (m, 1H), 7.74-7.69 (m, 1H), 7.41-7.36 (m,1H), 7.20 (dd, J = 7.4, 2.2 Hz, 1H), 6.66-6.61 (m, 1H), 5.36 (s, 1H),4.04-3.07 (m, 4H), 2.88-2.70 (m, 1H), 2.34 (s, 3H), 2.28-2.12 (m, 10H),1.89-1.74 (m, 1H). 138 (DMSO-d₆) δ 9.28 (s, 1H), 8.91 (s, 1H), 437.48.38-8.31 (m, 1H), 8.07-7.99 (m, 1H), 7.99-7.94 (m, 1H), 7.76-7.71 (m,1H), 7.42-7.37 (m, 1H), 7.18 (dd, J = 7.4, 2.1 Hz, 1H), 6.69-6.63 (m,1H), 5.41 (s, 1H), 3.94-3.82 (m, 2H), 3.71-3.62 (m, 2H), 2.65-2.51 (m,2H), 2.35 (s, 3H), 2.25 (s, 3H).

TABLE 2-25 139 (DMSO-d₆) δ 9.21 (s, 1H), 8.79 (s, 1H), 399.3 8.37-8.30(m, 1H), 8.10-8.05 (m, 1H), 8.05-8.02 (m, 1H), 7.75-7.70 (m, 1H),7.41-7.36 (m, 1H), 7.21 (dd, J = 7.4, 2.1 Hz, 1H), 6.67-6.62 (m, 1H),6.05 (s, 2H), 5.37 (s, 1H), 4.43-4.06 (m, 4H), 2.35 (s, 3H), 2.26 (s,3H). 140 (DMSO-d₆) δ 9.17 (s, 1H), 8.74 (s, 1H), 431.2 8.36-8.29 (m,1H), 8.09-8.03 (m, 1H), 8.05-7.98 (m, 1H), 7.74-7.69 (m, 1H), 7.41-7.35(m, 1H), 7.19 (dd, J = 7.5, 2.2 Hz, 1H), 6.64 (s, 1H), 5.36 (s, 1H),4.16-4.02 (m, 1H), 3.67-3.34 (m, 4H), 3.29 (s, 3H), 2.34 (s, 3H), 2.25(s, 3H), 2.12-2.04 (m, 2H). 141 (DMSO-d₆) δ 9.17 (s, 1H), 8.84 (s, 1H),441.3 8.36-8.30 (m, 1H), 8.05-8.00 (m, 1H), 7.77-7.71 (m, 2H), 7.43-7.38(m, 1H), 7.25 (dd, J = 7.4, 2.1 Hz, 1H), 6.61-6.56 (m, 1H), 5.61 (s,1H), 3.59-3.52 (m, 4H), 2.33 (s, 3H), 1.87-1.77 (m, 1H), 1.71-1.52 (m,6H), 1.03-0.93 (m, 2H), 0.77-0.65 (m, 2H). 142 (500 MHz, DMSO-d₆) δ 9.23(s, 1H), 8.71 (s, 1H), 429.4 8.37-8.32 (m, 1H), 8.09-8.03 (m, 2H),7.77-7.73 (m, 1H), 7.46-7.40 (m, 1H), 7.23 (dd, J = 7.4, 2.2 Hz, 1H),6.66-6.62 (m, 1H), 5.35 (s, 1H), 3.79-3.04 (m, 4H), 2.34 (s, 3H), 2.24(s, 3H), 1.81-1.75 (m, 2H), 1.12 (s, 6H).

TABLE 2-26 143 (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.75 (s, 1H), 403.28.37-8.29 (m, 1H), 8.14-8.09 (m, 1H), 8.02-7.95 (m, 1H), 7.75-7.69 (m,1H), 7.61 (t, J = 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2Hz, 1H), 6.33 (dd, J = 7.9, 0.7 Hz, 1H), 5.37 (s, 1H), 3.86 (s, 3H),3.53-3.36 (m, 4H), 2.00-1.92 (m, 4H). 144 (400 MHz, DMSO-d₆) δ 9.17 (s,1H), 8.81 (s, 1H), 417.2 8.35 (dd, J = 7.4, 0.8 Hz, 1H), 8.11-8.05 (m,1H), 7.82-7.76 (m, 1H), 7.75-7.70 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H),7.42-7.37 (m, 1H), 7.09 (dd, J = 7.4, 2.2 Hz, 1H), 6.34 (dd, J = 8.0,0.7 Hz, 1H), 5.64 (s, 1H), 3.85 (s, 3H), 3.59-3.51 (m, 4H), 1.70-1.51(m, 6H). 145 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.96 (s, 1H), 417.2 8.32(dd, J = 7.4, 0.8 Hz, 1H), 8.10-8.07 (m, 1H), 8.06-8.01 (m, 2H),7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.21 (dd, J = 7.4, 2.2 Hz, 1H),6.52-6.45 (m, 1H), 5.37 (s, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.47-3.42 (m,4H), 2.00-1.92 (m, 4H), 1.28 (t, J = 6.9 Hz, 3H). 146 (500 MHz, DMSO-d₆)δ 9.15 (s, 1H), 8.71 (s, 1H), 415.2 8.36-8.30 (m, 1H), 8.09-8.05 (m,1H), 8.06-8.00 (m, 1H), 7.74-7.70 (m, 1H), 7.42-7.35 (m, 1H), 7.19 (dd,J = 7.5, 2.2 Hz, 1H), 6.66-6.61 (m, 1H), 5.34 (s, 1H), 3.97-2.84 (m,4H), 2.39-2.30 (m, 4H), 2.24 (s, 3H), 2.15-2.05 (m, 1H), 1.65-1.54 (m,1H), 1.09 (d, J = 6.6 Hz, 3H). 147 (500 MHz, DMSO-d₆) δ 9.19-9.15 (m,1H), 429.2 8.73-8.67 (m, 1H), 8.36-8.32 (m, 1H), 8.18-8.14 (m, 1H),8.10-8.06 (m, 1H), 8.06-7.98 (m, 1H), 7.75-7.71 (m, 1H), 7.42-7.38 (m,1H), 7.23-7.17 (m, 1H), 6.67-6.61 (m, 1H), 5.36-5.32 (m, 1H), 3.87-2.83(m, 4H), 2.39-2.32 (m, 4H), 2.24 (s, 3H), 1.87-1.83 (m, 1H), 1.14-0.90(m, 6H).

TABLE 2-27 148 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.76 (s, 1H), 470.28.36-8.29 (m, 1H), 8.10-8.05 (m, 1H), 8.05-8.00 (m, 1H), 7.74-7.69 (m,1H), 7.41-7.35 (m, 1H), 7.20 (dd, J = 7.4, 2.2 Hz, 1H), 6.66-6.61 (m,1H), 5.35 (s, 1H), 4.06-3.12 (m, 9H), 2.86-2.81 (m, 1H), 2.60-2.52 (m,3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.21-2.13 (m, 1H), 1.95-1.86 (m, 1H).149 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.75 (s, 1H), 486.2 8.36-8.29 (m,1H), 8.10-8.04 (m, 1H), 8.04-7.98 (m, 1H), 7.74-7.69 (m, 1H), 7.41-7.35(m, 1H), 7.19 (dd, J = 7.5, 2.2 Hz, 1H), 6.66-6.61 (m, 1H), 5.36 (s,1H), 4.03-3.45 (m, 8H), 3.24-3.18 (m, 1H), 2.95-2.90 (m, 1H), 2.59-2.38(m, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.22-2.14 (m, 1H), 1.89-1.76 (m,1H). 150 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.66 (s, 1H), 417.18.37-8.30 (m, 1H), 8.13-8.07 (m, 1H), 7.99-7.92 (m, 1H), 7.75-7.69 (m,1H), 7.60 (t, J = 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2Hz, 1H), 6.34-6.24 (m, 1H), 5.37 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H),3.58-3.35 (m, 4H), 2.00-1.92 (m, 4H), 1.32 (t, J = 7.0 Hz, 3H). 151 (400MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.70 (s, 1H), 431.4 8.40-8.30 (m, 1H),8.13-8.07 (m, 1H), 7.99-7.92 (m, 1H), 7.74-7.69 (m, 1H), 7.60 (t, J =8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz, 1H),6.34-6.27 (m, 1H), 5.37 (s, 1H), 4.22 (t, J = 6.7 Hz, 2H), 3.46-3.41 (m,4H), 2.00-1.92 (m, 4H), 1.80-1.66 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 152(400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.73 (s, 1H), 447.3 8.37-8.30 (m,1H), 8.13-8.08 (m, 1H), 8.00-7.93 (m, 1H), 7.74-7.69 (m, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.42-7.34 (m, 1H), 7.13 (dd, J = 7.6, 2.1 Hz, 1H),6.36-6.29 (m, 1H), 5.38 (s, 1H), 4.44-4.36 (m, 2H), 3.66 (t, J = 4.8 Hz,2H), 3.58-3.38 (m, 4H), 3.31 (s, 3H), 2.00-1.92 (m, 4H).

TABLE 2-28 153 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.66 (s, 1H), 431.18.37-8.30 (m, 1H), 8.14-8.09 (m, 1H), 7.97-7.90 (m, 1H), 7.74-7.69 (m,1H), 7.57 (t, J = 7.9 Hz, 1H), 7.41-7.36 (m, 1H), 7.11 (dd, J = 7.4, 2.2Hz, 1H), 6.29-6.22 (m, 1H), 5.37 (s, 1H), 5.36-5.22 (m, 1H), 3.61-3.39(m, 4H), 2.00-1.92 (m, 4H), 1.29 (d, J = 6.2 Hz, 6H). 154 (400 MHz,DMSO-d₆) δ 9.15 (s, 1H), 8.74 (s, 1H), 502.1 8.37-8.30 (m, 1H),8.13-8.07 (m, 1H), 7.99-7.92 (m, 1H), 7.74-7.69 (m, 1H), 7.60 (t, J =8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz, 1H),6.35-6.28 (m, 1H), 5.37 (s, 1H), 4.39 (t, J = 5.9 Hz, 2H), 3.61-3.54 (m,4H), 3.51-3.36 (m, 4H), 2.68 (t, J = 5.9 Hz, 2H), 2.51-2.43 (m, 4H),2.00-1.92 (m, 4H). 155 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.74 (s, 1H),460.2 8.37-8.30 (m, 1H), 8.12-8.07 (m, 1H), 7.99-7.92 (m, 1H), 7.74-7.69(m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.5,2.2 Hz, 1H), 6.34-6.27 (m, 1H), 5.38 (s, 1H), 4.35 (t, J = 5.9 Hz, 2H),3.56-3.37 (m, 4H), 2.62 (t, J = 5.9 Hz, 2H), 2.22 (s, 6H), 2.00-1.90 (m,4H). 156 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.71 (s, 1H), 489.18.37-8.30 (m, 1H), 8.11-8.06 (m, 1H), 8.00-7.93 (m, 1H), 7.74-7.69 (m,1H), 7.60 (t, J = 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.14 (dd, J = 7.4, 2.2Hz, 1H), 6.36-6.29 (m, 1H), 5.38 (s, 1H), 4.32 (t, J = 5.1 Hz, 2H), 3.64(t, J = 5.1 Hz, 2H), 3.58-3.38 (m, 4H), 2.00-1.92 (m, 4H), 1.16 (s, 9H).157 (500 MHz, DMSO-d₆) δ 9.19-9.15 (m, 1H), 8.71 (s, 433.2 1H),8.37-8.31 (m, 1H), 8.12-8.08 (m, 1H), 8.00-7.93 (m, 1H), 7.74-7.70 (m,1H), 7.64-7.57 (m, 1H), 7.41-7.37 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz,1H), 6.36-6.30 (m, 1H), 5.37 (s, 1H), 4.82-4.76 (m, 1H), 4.29 (t, J =5.2 Hz, 2H), 3.75-3.68 (m, 2H), 3.62-3.35 (m, 4H), 1.99-1.93 (m, 4H).

TABLE 2-29 158 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.74 (s, 1H), 445.38.37-8.30 (m, 1H), 8.14-8.09 (m, 1H), 7.99-7.92 (m, 1H), 7.74-7.69 (m,1H), 7.60 (t, J = 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.14 (dd, J = 7.4, 2.2Hz, 1H), 6.35-6.28 (m, 1H), 5.37 (s, 1H), 4.05 (d, J = 6.7 Hz, 2H),3.64-3.35 (m, 4H), 2.12-1.86 (m, 5H), 0.98 (d, J = 6.7 Hz, 6H). 159 (500MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.87 (s, 1H), 431.1 8.33 (dd, J = 7.4, 0.8Hz, 1H), 8.26-8.20 (m, 1H), 8.09-8.05 (m, 1H), 7.74-7.70 (m, 1H),7.65-7.58 (m, 1H), 7.41-7.37 (m, 1H), 7.21 (dd, J = 7.4, 2.2 Hz, 1H),6.85-6.79 (m, 1H), 5.36 (s, 1H), 3.70 (t, J = 6.8 Hz, 2H), 3.56-3.38 (m,4H), 3.25 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 1.99-1.93 (m, 4H). 160 (500MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.86 (s, 1H), 445.1 8.39-8.34 (m, 1H),8.26-8.21 (m, 1H), 8.16-8.12 (m, 1H), 7.80-7.75 (m, 1H), 7.67-7.58 (m,1H), 7.48-7.44 (m, 1H), 7.29 (dd, J = 7.6, 2.2 Hz, 1H), 6.86-6.81 (m,1H), 5.38 (s, 1H), 3.72 (t, J = 7.0 Hz, 2H), 3.63-3.37 (m, 6H), 2.87 (t,J = 6.9 Hz, 2H), 2.01-1.93 (m, 4H), 1.09 (t, J = 7.0 Hz, 3H). 161 (500MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.81 (s, 1H), 429.3 8.40-8.35 (m, 1H),8.26-8.20 (m, 1H), 8.18-8.14 (m, 1H), 7.81-7.77 (m, 1H), 7.65-7.58 (m,1H), 7.51-7.47 (m, 1H), 7.34 (dd, J = 7.5, 2.2 Hz, 1H), 6.78-6.73 (m,1H), 5.39 (s, 1H), 3.55-3.37 (m, 4H), 2.53-2.49 (m, 2H), 2.14-2.02 (m,1H), 2.00-1.93 (m, 4H), 0.90 (d, J = 6.6 Hz, 6H). 162 (500 MHz, DMSO-d₆)δ 9.16 (s, 1H), 8.65 (s, 1H), 443.4 8.37-8.30 (m, 1H), 8.29-8.22 (m,1H), 8.10-8.05 (m, 1H), 7.74-7.70 (m, 1H), 7.66-7.57 (m, 1H), 7.41-7.37(m, 1H), 7.19 (dd, J = 7.4, 2.2 Hz, 1H), 6.74 (dd, J = 7.5, 0.9 Hz, 1H),5.36 (s, 1H), 3.60-3.37 (m, 4H), 2.54 (s, 2H), 2.01-1.88 (m, 4H), 0.95(s, 9H).

TABLE 2-30 163 (500 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.90 (s, 1H), 470.68.36-8.30 (m, 1H), 8.26-8.19 (m, 4H), 8.11-8.07 (m, 1H), 7.74-7.70 (m,1H), 7.65-7.58 (m, 1H), 7.41-7.37 (m, 1H), 7.18 (dd, J = 7.4, 2.1 Hz,1H), 6.86-6.81 (m, 1H), 5.37 (s, 1H), 3.79-3.05 (m, 4H), 2.96-2.83 (m,4H), 2.69-2.63 (m, 4H), 1.99-1.93 (m, 4H), 1.79-1.70 (m, 4H). 164 (400MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.60 (dd, J = 4.9, 445.3 1.9 Hz, 1H), 8.55(s, 1H), 8.46-8.40 (m, 1H), 8.30-8.22 (m, 1H), 7.77-7.72 (m, 1H),7.70-7.64 (m, 1H), 7.40-7.35 (m, 1H), 7.16-7.08 (m, 1H), 7.01 (dd, J =7.4, 2.2 Hz, 1H), 5.34 (s, 1H), 4.51 (s, 2H), 3.39 (t, J = 6.3 Hz, 2H),3.36-3.27 (m, 4H), 1.94-1.88 (m, 4H), 1.63-1.49 (m, 2H), 0.91 (t, J =7.4 Hz, 3H). 165 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.85 (s, 1H), 429.38.32 (dd, J = 7.4, 0.8 Hz, 1H), 8.25-8.18 (m, 1H), 8.10-8.04 (m, 1H),7.75-7.69 (m, 1H), 7.65-7.56 (m, 1H), 7.41-7.36 (m, 1H), 7.26-7.19 (m,1H), 6.78 (dd, J = 7.4, 0.9 Hz, 1H), 5.36 (s, 1H), 3.55-3.36 (m, 4H),2.67-2.60 (m, 2H), 2.00-1.92 (m, 4H), 1.73-1.60 (m, 2H), 1.41-1.27 (m,2H), 0.91 (t, J = 7.4 Hz, 3H). 166 (400 MHz, DMSO-d₆) δ 9.19 (s, 1H),8.83 (s, 1H), 387.2 8.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.05-7.99 (m, 2H),7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.20-7.12 (m, 1H), 6.66-6.61 (m,1H), 5.24 (s, 1H), 4.05-3.96 (m, 4H), 2.42-2.31 (m, 5H), 2.23 (s, 3H).167 (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.92 (s, 1H), 415.3 8.33 (dd, J =7.4, 0.8 Hz, 1H), 8.20-8.13 (m, 1H), 8.08-8.02 (m, 1H), 7.75-7.70 (m,1H), 7.62-7.53 (m, 1H), 7.42-7.37 (m, 1H), 7.22-7.15 (m, 1H), 6.78 (dd,J = 7.4, 0.9 Hz, 1H), 5.24 (s, 1H), 4.04-3.95 (m, 4H), 2.68-2.59 (m,2H), 2.42-2.29 (m, 2H), 1.72-1.59 (m, 2H), 1.33 (h, J = 7.3 Hz, 2H),0.91 (t, J = 7.3 Hz, 3H).

TABLE 2-31 168 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.81 (s, 1H), 457.38.36-8.29 (m, 1H), 8.23-8.16 (m, 1H), 8.08-8.02 (m, 1H), 7.75-7.70 (m,1H), 7.65-7.56 (m, 1H), 7.42-7.36 (m, 1H), 7.21 (dd, J = 7.4, 2.2 Hz,1H), 6.78 (dd, J = 7.4, 0.9 Hz, 1H), 5.34 (s, 1H), 3.80-2.95 (m, 4H),2.68-2.59 (m, 2H), 1.82-1.73 (m, 2H), 1.73-1.60 (m, 2H), 1.41-1.27 (m,2H), 1.12 (s, 6H), 0.91 (t, J = 7.3 Hz, 3H). 169 (400 MHz, DMSO-d₆) δ9.16 (s, 1H), 8.84 (s, 1H), 499.3 8.33 (dd, J = 7.2, 0.9 Hz, 1H),8.23-8.16 (m, 1H), 8.09-8.03 (m, 1H), 7.75-7.69 (m, 1H), 7.65-7.56 (m,1H), 7.43-7.36 (m, 1H), 7.21 (dd, J = 7.4, 2.2 Hz, 1H), 6.78 (dd, J =7.4, 0.9 Hz, 1H), 5.37 (s, 1H), 3.71-3.51 (m, 4H), 3.51-3.19 (m, 4H),2.68-2.59 (m, 2H), 1.95-1.86 (m, 2H), 1.71-1.62 (m, 2H), 1.62-1.49 (m,4H), 1.41-1.27 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 170 (400 MHz, DMSO-d₆)δ 9.15 (s, 1H), 8.92 (s, 1H), 429.3 8.36-8.27 (m, 2H), 8.12 (dd, J =5.0, 0.7 Hz, 1H), 8.08-8.03 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m,1H), 7.18 (dd, J = 7.4, 2.2 Hz, 1H), 6.82-6.75 (m, 1H), 5.35 (s, 1H),3.75-3.07 (m, 4H), 2.60 (q, J = 7.6 Hz, 2H), 1.83-1.75 (m, 2H), 1.17 (t,J = 7.6 Hz, 3H), 1.12 (s, 6H). 171 (400 MHz, DMSO-d₆) δ 9.13 (s, 1H),8.59-8.53 (m, 431.3 2H), 8.36-8.33 (m, 1H), 8.29-8.23 (m, 1H), 7.79-7.72(m, 1H), 7.70-7.64 (m, 1H), 7.40-7.35 (m, 1H), 7.18-7.10 (m, 1H),7.06-6.99 (m, 1H), 5.33 (s, 1H), 4.51 (s, 2H), 3.48 (q, J = 7.0 Hz, 2H),3.33 (s, 4H), 1.95-1.87 (m, 4H), 1.16 (t, J = 7.0 Hz, 3H). 172 (500 MHz,DMSO-d₆) δ 9.16 (s, 1H), 8.85 (s, 1H), 444.4 8.35-8.30 (m, 1H),8.24-8.19 (m, 1H), 8.10-8.05 (m, 1H), 7.74-7.70 (m, 1H), 7.63-7.56 (m,1H), 7.41-7.36 (m, 1H), 7.21 (dd, J = 7.4, 2.2 Hz, 1H), 6.84-6.79 (m,1H), 5.36 (s, 1H), 3.61-3.37 (m, 4H), 2.80-2.73 (m, 2H), 2.63-2.56 (m,2H), 2.18 (s, 6H), 1.99-1.93 (m, 4H).

TABLE 2-32 173 (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.81 (s, 1H), 483.38.32 (dd, J = 7.4, 0.8 Hz, 1H), 8.22-8.15 (m, 1H), 8.08-8.02 (m, 1H),7.75-7.69 (m, 1H), 7.64-7.56 (m, 1H), 7.41-7.36 (m, 1H), 7.21 (dd, J =7.5, 2.2 Hz, 1H), 6.78 (dd, J = 7.4, 0.8 Hz, 1H), 5.34 (s, 1H),3.76-3.03 (m, 4H), 2.68-2.59 (m, 2H), 1.90-1.82 (m, 2H), 1.73-1.52 (m,10H), 1.41-1.27 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 174 (400 MHz,DMSO-d₆) δ 9.14 (s, 1H), 8.73 (s, 1H), 455.3 8.32 (dd, J = 7.4, 0.8 Hz,1H), 8.10-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.41-7.35(m, 1H), 7.19 (dd, J = 7.4, 2.2 Hz, 1H), 6.66-6.60 (m, 1H), 5.34 (s,1H), 3.68-3.10 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 1.92-1.83 (m, 2H),1.72-1.55 (m, 8H). 175 (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.77 (s, 1H),471.2 8.33 (dd, J = 7.3, 0.8 Hz, 1H), 8.12-8.07 (m, 1H), 8.06-8.01 (m,1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.20 (dd, J = 7.5, 2.2 Hz,1H), 6.67-6.61 (m, 1H), 5.37 (s, 1H), 3.73-3.63 (m, 2H), 3.60-3.51 (m,2H), 3.50-3.22 (m, 4H), 2.34 (s, 3H), 2.25 (s, 3H), 1.95-1.87 (m, 2H),1.61-1.53 (m, 4H). 176 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.73 (s, 1H),441.3 8.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.05-8.03 (m, 1H), 8.02-8.01 (m,1H), 7.75-7.69 (m, 1H), 7.41-7.35 (m, 1H), 7.18 (dd, J = 7.4, 2.2 Hz,1H), 6.66-6.60 (m, 1H), 5.36 (s, 1H), 3.67-3.62 (m, 2H), 3.25-3.15 (m,2H), 2.80-2.71 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.90-1.43 (m, 6H).177 (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.81 (s, 1H), 415.2 8.37-8.30 (m,1H), 8.07-7.99 (m, 2H), 7.76-7.70 (m, 1H), 7.43-7.36 (m, 1H), 7.17 (dd,J = 7.4, 2.2 Hz, 1H), 6.67-6.61 (m, 1H), 5.25 (s, 1H), 3.70 (s, 4H),2.34 (s, 3H), 2.24 (s, 3H), 1.31 (s, 6H).

TABLE 2-33 178 (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.89 (s, 1H), 429.38.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.06-7.98 (m, 2H), 7.75-7.70 (m, 1H),7.41-7.36 (m, 1H), 7.16 (dd, J = 7.4, 2.2 Hz, 1H), 6.67-6.62 (m, 1H),5.26 (s, 1H), 4.75 (s, 4H), 4.17 (s, 4H), 2.34 (s, 3H), 2.26 (s, 3H).179 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.81 (s, 1H), 469.4 8.36-8.29 (m,1H), 8.21-8.14 (m, 1H), 8.08-8.02 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.57(m, 1H), 7.41-7.36 (m, 1H), 7.21 (dd, J = 7.5, 2.2 Hz 1H), 6.81-6.74 (m,1H), 5.36 (s, 1H), 3.69-3.60 (m, 2H), 3.21 (d, J = 10.8 Hz, 2H),2.83-2.71 (m, 2H), 2.68-2.56 (m, 2H), 1.92-1.28 (m, 10H), 0.91 (t, J =7.3 Hz, 3H). 180 (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.91 (s, 1H), 443.38.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.20-8.13 (m, 1H), 8.08-8.03 (m, 1H),7.75-7.70 (m, 1H), 7.63-7.54 (m, 1H), 7.42-7.36 (m, 1H), 7.20 (dd, J =7.4, 2.2 Hz, 1H), 6.78 (dd, J = 7.4, 0.8 Hz, 1H), 5.25 (s, 1H), 3.70 (s,4H), 2.68-2.59 (m, 2H), 1.72-1.60 (m, 2H), 1.41-1.26 (m, 8H), 0.91 (t, J= 7.3 Hz, 3H). 181 (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.98 (s, 1H),457.3 8.33 (dd, J = 7.5, 0.9 Hz, 1H), 8.20-8.13 (m, 1H), 8.09-8.04 (m,1H), 7.75-7.70 (m, 1H), 7.64-7.55 (m, 1H), 7.42-7.37 (m, 1H), 7.19 (dd,J = 7.4, 2.2 Hz, 1H), 6.83-6.76 (m, 1H), 5.29-5.24 (m, 1H), 4.74 (s,4H), 4.17 (s, 4H), 2.68-2.59 (m, 2H), 1.72-1.60 (m, 2H), 1.41-1.26 (m,2H), 0.91 (t, J = 7.3 Hz, 3H). 182 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H),8.82 (s, 1H), 443.3 8.37-8.29 (m, 1H), 8.06-8.00 (m, 1H), 7.92-7.86 (m,1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.13 (dd, J = 7.4, 2.2 Hz,1H), 6.67-6.61 (m, 1H), 5.63 (s, 1H), 3.59-3.51 (m, 4H), 2.34 (s, 3H),2.23 (s, 3H), 1.41-1.33 (m, 4H), 0.99 (s, 6H).

TABLE 2-34 183 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.82 (s, 1H), 429.38.37-8.29 (m, 1H), 8.05-7.99 (m, 1H), 7.91-7.86 (m, 1H), 7.75-7.70 (m,1H), 7.41-7.36 (m, 1H), 7.12 (dd, J = 7.4, 2.2 Hz, 1H), 6.67-6.61 (m,1H), 5.63 (s, 1H), 4.27-4.18 (m, 2H), 2.94-2.82 (m, 2H), 2.34 (s, 3H),2.23 (s, 3H), 1.73-1.59 (m, 3H), 1.18-1.04 (m, 2H), 0.93 (d, J = 6.0 Hz,3H). 184 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.85 (s, 1H), 429.38.37-8.29 (m, 1H), 8.07-8.01 (m, 1H), 7.93-7.88 (m, 1H), 7.75-7.69 (m,1H), 7.41-7.36 (m, 1H), 7.14 (dd, J = 7.4, 2.2 Hz, 1H), 6.67-6.62 (m,1H), 5.62 (s, 1H), 4.22-4.06 (m, 2H), 2.93-2.81 (m, 1H), 2.61-2.52 (m,1H), 2.34 (s, 3H), 2.24 (s, 3H), 1.87-1.37 (m, 4H), 1.26-1.10 (m, 1H),0.93 (d, J = 6.6 Hz, 3H). 185 (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.83(s, 1H), 419.5 8.37-8.30 (m, 1H), 8.07-8.01 (m, 2H), 7.75-7.70 (m, 1H),7.43-7.34 (m, 1H), 7.23-7.16 (m, 1H), 6.67-6.62 (m, 1H), 5.58-5.33 (m,2H), 3.84-3.41 (m, 4H), 2.35 (s, 3H), 2.32-2.07 (m, 5H). 186 (400 MHz,DMSO-d₆) δ 9.22 (s, 1H), 8.84 (s, 1H), 419.4 8.34 (dd, J = 7.3, 0.8 Hz,1H), 8.07-8.01 (m, 2H), 7.75-7.70 (m, 1H), 7.42-7.36 (m, 1H), 7.20 (dd,J = 7.4, 2.2 Hz, 1H), 6.67-6.62 (m, 1H), 5.57-5.34 (m, 2H), 3.88-3.39(m, 4H), 2.39-2.07 (m, 8H). 187 (500 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.74(s, 1H), 457.1 8.42-8.37 (m, 1H), 8.15-8.11 (m, 1H), 7.93-7.89 (m, 1H),7.82-7.78 (m, 1H), 7.53-7.47 (m, 1H), 7.28-7.22 (m, 1H), 6.68-6.62 (m,1H), 5.65 (s, 1H), 3.59-3.49 (m, 4H), 2.59 (t, J = 7.7 Hz, 2H), 2.24 (s,3H), 1.72-1.52 (m, 8H), 1.39-1.28 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

TABLE 2-35 188 (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.73 (s, 1H), 457.28.38-8.33 (m, 1H), 8.08-8.04 (m, 1H), 7.98-7.90 (m, 1H), 7.77-7.72 (m,1H), 7.44-7.39 (m, 1H), 7.16 (dd, J = 7.5, 2.2 Hz, 1H), 6.64-6.58 (m,1H), 5.63 (s, 1H), 3.58-3.49 (m, 4H), 2.46 (d, J = 7.1 Hz, 2H), 2.25 (s,3H), 2.13-2.01 (m, 1H), 1.70-1.52 (m, 6H), 0.90 (d, J = 6.6 Hz, 6H). 189(500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.74 (s, 1H), 429.1 8.44-8.37 (m,1H), 8.15-8.10 (m, 1H), 7.93-7.89 (m, 1H), 7.82-7.76 (m, 1H), 7.51-7.47(m, 1H), 7.25 (dd, J = 7.4, 2.1 Hz, 1H), 6.66 (s, 1H), 5.66 (s, 1H),3.59-3.53 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.70-1.52 (m,6H), 1.22 (t, J = 7.5 Hz, 3H). 190 (500 MHz, DMSO-d₆) δ 9.78 (s, 1H),8.92 (s, 1H), 431.0 8.51-8.47 (m, 1H), 8.33-8.29 (m, 1H), 7.95-7.91 (m,1H), 7.75-7.71 (m, 1H), 7.70-7.66 (m, 1H), 7.58-7.52 (m, 1H), 6.46-6.41(m, 1H), 5.72 (s, 1H), 3.77 (s, 3H), 3.61-3.55 (m, 4H), 2.33 (s, 3H),1.70-1.50 (m, 6H). 191 (500 MHz, DMSO-d₆) δ 9.91 (s, 1H), 9.14 (s, 1H),449.0 8.70-7.58 (m, 6H), 6.68-6.63 (m, 1H), 5.75 (s, 1H), 5.34 (d, J =47.0 Hz, 2H), 3.83 (s, 3H), 3.63-3.57 (m, 4H), 1.71-1.52 (m, 6H). 192(400 MHz, Chloroform-d) δ 9.43 (s, 1H), 8.76 (s, 417.3 1H), 8.35-8.28(m, 1H), 8.04-7.96 (m, 1H), 7.88-7.81 (m, 1H), 7.57-7.49 (m, 2H),7.50-7.42 (m, 1H), 7.10 (dd, J = 7.5, 4.9 Hz, 1H), 6.86 (dd, J = 7.3,2.2 Hz, 1H), 5.67 (s, 1H), 4.67 (s, 2H), 3.43-3.35 (m, 4H), 1.60-1.45(m, 6H).

TABLE 2-36 193 (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.70 (s, 1H), 429.18.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.10-8.06 (m, 1H), 8.03-7.99 (m, 1H),7.74-7.70 (m, 1H), 7.41-7.36 (m, 1H), 7.18 (dd, J = 7.3, 2.2 Hz, 1H),6.65-6.61 (m, 1H), 5.33 (s, 1H), 3.12-2.81 (m, 4H), 2.34 (s, 3H), 2.24(s, 3H), 1.87-1.83 (m, 2H), 1.08 (d, J = 5.8 Hz, 6H). 194 (500 MHz,DMSO-d₆) δ 9.19 (s, 1H), 8.76 (s, 1H), 459.0 8.36-8.31 (m, 1H),8.05-8.00 (m, 2H), 7.75-7.70 (m, 1H), 7.41-7.37 (m, 1H), 7.19 (dd, J =7.4, 2.2 Hz, 1H), 6.66-6.62 (m, 1H), 5.37 (s, 1H), 4.41-4.17 (m, 2H),3.91-3.39 (m, 8H), 2.34 (s, 3H), 2.24 (s, 3H). 195 (500 MHz, DMSO-d₆) δ9.27 (s, 1H), 9.11 (s, 1H), 423.0 9.04 (s, 1H), 8.39-8.34 (m, 1H),8.01-7.97 (m, 1H), 7.94-7.90 (m, 1H), 7.74 (s, 1H), 7.68-7.62 (m, 2H),7.42-7.38 (m, 1H), 7.35-7.26 (m, 2H), 7.15 (dd, J = 7.4, 2.1 Hz, 1H),7.02-6.95 (m, 1H), 6.65 (s, 1H), 5.82 (s, 1H), 2.36 (s, 3H), 2.20 (s,3H). 196 (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.64 (s, 1H), 437.1 8.32(dd, J = 7.3, 0.9 Hz, 1H), 7.97-7.91 (m, 2H), 7.73-7.69 (m, 1H),7.48-7.44 (m, 1H), 7.40-7.30 (m, 5H), 7.27-7.19 (m, 1H), 7.14 (dd, J =7.5, 2.2 Hz, 1H), 6.62-6.58 (m, 1H), 5.51 (s, 1H), 4.53 (s, 2H), 2.32(s, 3H), 2.14 (s, 3H). 197 (500 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.89 (s,1H), 473.1 8.45-8.40 (m, 1H), 8.25-8.21 (m, 1H), 7.88-7.84 (m, 1H),7.77-7.72 (m, 1H), 7.59-7.55 (m, 1H), 7.42-7.38 (m, 1H), 6.42-6.38 (m,1H), 5.67 (s, 1H), 3.76 (s, 3H), 3.63-3.55 (m, 4H), 2.60-2.53 (m, 2H),1.70-1.52 (m, 8H), 1.39-1.27 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

TABLE 2-37 198 (500 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.58 (s, 1H), 430.18.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.05-8.01 (m, 1H), 8.01-7.95 (m, 1H),7.74-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.40-7.35 (m, 1H), 7.16 (dd, J =7.4, 2.2 Hz, 1H), 6.66-6.60 (m, 1H), 5.83 (s, 1H), 3.04-2.40 (m, 4H),2.34 (s, 3H), 2.26 (s, 3H), 1.74-1.52 (m, 6H). 199 (500 MHz, DMSO-d₆) δ9.27 (s, 1H), 8.66 (s, 1H), 432.1 8.33 (dd, J = 7.4, 0.8 Hz, 1H),8.06-8.02 (m, 1H), 8.00-7.96 (m, 1H), 7.82-7.78 (m, 1H), 7.74-7.69 (m,1H), 7.40-7.36 (m, 1H), 7.16 (dd, J = 7.5, 2.2 Hz, 1H), 6.67-6.61 (m,1H), 5.88 (s, 1H), 3.69 (s, 4H), 2.82-2.78 (m, 4H), 2.34 (s, 3H), 2.26(s, 3H). 200 (500 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.31 (s, 1H), 411.99.09-9.05 (m, 1H), 8.34-8.29 (m, 1H), 8.09-8.04 (m, 1H), 7.93-7.89 (m,1H), 7.74-7.70 (m, 1H), 7.41-7.37 (m, 1H), 7.14 (dd, J = 7.4, 2.2 Hz,1H), 6.91-6.85 (m, 2H), 6.66-6.62 (m, 1H), 6.16-6.11 (m, 2H), 5.06 (s,1H), 2.34 (s, 3H), 2.23 (s, 3H). 201 (500 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.81 (s, 1H), 471.1 8.37-8.30 (m, 1H), 8.06-8.01 (m, 1H), 7.97-7.88 (m,1H), 7.75-7.71 (m, 1H), 7.40-7.36 (m, 1H), 7.17 (dd, J = 7.5, 2.2 Hz,1H), 6.69-6.61 (m, 1H), 5.61 (s, 1H), 3.59-3.49 (m, 4H), 2.64-2.52 (m,4H), 1.70-1.51 (m, 8H), 1.41-1.28 (m, 2H), 1.12 (t, J = 7.6 Hz, 3H),0.91 (t, J = 7.5 Hz, 3H). 202 (500 MHz, DMSO-d₆) δ 9.21 (s, 1H), 9.15(s, 1H), 419.0 8.38-8.32 (m, 1H), 8.08-8.04 (m, 1H), 8.04-7.97 (m, 1H),7.76-7.72 (m, 1H), 7.59-7.52 (m, 1H), 7.45-7.40 (m, 1H), 7.18 (dd, J =7.6, 2.3 Hz, 1H), 5.63 (s, 1H), 3.56-3.50 (m, 4H), 2.38 (d, J = 2.9 Hz,3H), 1.70-1.48 (m, 6H).

TABLE 2-38 203 (500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.22 (s, 1H), 434.98.38-8.33 (m, 1H), 8.09-8.03 (m, 2H), 7.77-7.74 (m, 1H), 7.74-7.70 (m,1H), 7.43 (s, 1H), 7.21-7.16 (m, 1H), 5.65 (s, 1H), 3.56-3.50 (m, 4H),2.47 (s, 3H), 1.71-1.50 (m, 6H). 204 (400 MHz, DMSO-d₆) δ 9.36 (s, 1H),9.12 (s, 1H), 419.0 8.43-8.36 (m, 1H), 8.18-8.15 (m, 1H), 8.15-8.12 (m,1H), 8.11-8.07 (m, 1H), 7.81-7.76 (m, 1H), 7.53-7.46 (m, 1H), 7.22-7.14(m, 1H), 5.66 (s, 1H), 3.61-3.51 (m, 4H), 2.24 (s, 3H), 1.74-1.50 (m,6H). 205 (500 MHz, DMSO-d₆) δ 9.50 (s, 1H), 9.20 (s, 1H), 435.18.36-8.31 (m, 1H), 8.21-8.17 (m, 1H), 8.00-7.95 (m, 1H), 7.75-7.71 (m,1H), 7.41-7.37 (m, 1H), 7.22 (dd, J = 7.4, 2.1 Hz, 1H), 6.93-6.89 (m,1H), 5.65 (s, 1H), 3.58-3.49 (m, 4H), 2.39 (s, 3H), 1.71-1.50 (m, 6H).206 (500 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.60 (s, 1H), 416.1 8.38-8.33 (m,1H), 8.10-8.06 (m, 1H), 8.04-7.97 (m, 1H), 7.77-7.70 (m, 1H), 7.69-7.65(m, 1H), 7.45-7.41 (m, 1H), 7.22-7.16 (m, 1H), 6.63 (s, 1H), 5.88 (s,1H), 2.88-2.84 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.81-1.75 (m, 4H).207 (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 9.05 (s, 1H), 457.5 8.32 (dd, J =7.5, 0.8 Hz, 1H), 8.17-8.11 (m, 1H), 8.08-8.06 (m, 1H), 8.06-8.02 (m,1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.22 (dd, J = 7.4, 2.2 Hz,1H), 6.50 (dd, J = 5.7, 2.4 Hz, 1H), 5.36 (s, 1H), 3.81 (s, 3H),3.66-3.21 (m, 4H), 1.97-1.50 (m, 10H).

TABLE 2-39 208 (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.92 (s, 1H), 455.58.36-8.32 (m, 1H), 8.32-8.28 (m, 1H), 8.15-8.10 (m, 1H), 8.10-8.06 (m,1H), 7.76-7.71 (m, 1H), 7.43-7.38 (m, 1H), 7.21 (dd, J = 7.5, 2.2 Hz,1H), 6.79 (dd, J = 5.1, 1.5 Hz, 1H), 5.36 (s, 1H), 3.64-3.19 (m, 4H),2.60 (q, J = 7.6 Hz, 2H), 1.95-1.51 (m, 10H), 1.17 (t, J = 7.6 Hz, 3H).209 (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 9.02 (s, 1H), 431.4 8.35-8.28 (m,1H), 8.16-8.10 (m, 1H), 8.07-8.05 (m, 1H), 8.05-8.03 (m, 1H), 7.75-7.69(m, 1H), 7.41-7.36 (m, 1H), 7.22 (dd, J = 7.4, 2.2 Hz, 1H), 6.51 (dd, J= 5.8, 2.4 Hz, 1H), 5.36 (s, 1H), 3.81 (s, 3H), 3.67-3.19 (m, 4H),1.82-1.74 (m, 2H), 1.11 (s, 6H). 210 (500 MHz, DMSO-d₆) δ 9.56 (s, 1H),9.20 (s, 1H), 434.9 8.37-8.31 (m, 1H), 8.09-8.05 (m, 1H), 8.04-8.02 (m,1H), 7.75-7.71 (m, 1H), 7.41-7.37 (m, 1H), 7.11 (dd, J = 7.4, 2.1 Hz,1H), 6.87-6.83 (m, 1H), 5.65 (s, 1H), 3.58-3.52 (m, 4H), 2.27 (s, 3H),1.73-1.46 (m, 6H). 211 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.90 (s, 1H),443.5 8.34 (dd, J = 7.4, 0.8 Hz, 1H), 8.08-7.99 (m, 2H), 7.75-7.70 (m,1H), 7.65-7.56 (m, 1H), 7.42-7.37 (m, 1H), 7.16 (dd, J = 7.4, 2.2 Hz,1H), 6.76 (dd, J = 7.4, 0.8 Hz, 1H), 5.62 (s, 1H), 3.58-3.50 (m, 4H),2.55-2.49 (m, 2H), 2.16-2.01 (m, 1H), 1.69-1.50 (m, 6H), 0.90 (d, J =6.6 Hz, 6H). 212 (500 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.67 (s, 1H), 443.38.48-8.43 (m, 1H), 8.31-8.27 (m, 1H), 8.14-8.10 (m, 1H), 7.91-7.87 (m,1H), 7.65-7.61 (m, 1H), 7.48-7.42 (m, 1H), 6.65-6.61 (m, 1H), 5.42 (s,1H), 3.75-3.08 (m, 4H), 2.46 (d, J = 7.2 Hz, 2H), 2.27 (s, 3H),2.11-2.02 (m, 1H), 2.01-1.96 (m, 4H), 0.90 (d, J = 6.6 Hz, 6H).

TABLE 2-40 213 (500 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.66 (s, 1H), 471.48.48-8.43 (m, 1H), 8.30-8.26 (m, 1H), 8.13-8.09 (m, 1H), 7.90-7.86 (m,1H), 7.64-7.60 (m, 1H), 7.47-7.41 (m, 1H), 6.65-6.61 (m, 1H), 5.40 (s,1H), 3.92-2.96 (m, 4H), 2.46 (d, J = 7.2 Hz, 2H), 2.27 (s, 3H),2.11-2.02 (m, 1H), 1.83-1.76 (m, 2H), 1.13 (s, 6H), 0.90 (d, J = 6.6 Hz,6H). 214 (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.67 (s, 1H), 415.38.43-8.38 (m, 1H), 8.21-8.17 (m, 1H), 8.12-8.08 (m, 1H), 7.84-7.80 (m,1H), 7.55-7.51 (m, 1H), 7.37-7.31 (m, 1H), 6.68-6.64 (m, 1H), 5.40 (s,1H), 3.69-3.21 (m, 4H), 2.62 (q, J = 7.5 Hz, 2H), 2.26 (s, 3H),2.00-1.94 (m, 4H), 1.22 (t, J = 7.6 Hz, 3H). 215 (500 MHz, DMSO-d₆) δ9.46 (s, 1H), 8.65 (s, 1H), 443.3 8.44-8.39 (m, 1H), 8.21-8.17 (m, 1H),8.11-8.07 (m, 1H), 7.85-7.81 (m, 1H), 7.56-7.52 (m, 1H), 7.40-7.28 (m,1H), 6.69-6.65 (m, 1H), 5.38 (s, 1H), 3.78-3.10 (m, 4H), 2.62 (q, J =7.5 Hz, 2H), 2.26 (s, 3H), 1.82-1.76 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H),1.12 (s, 6H). 216 (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.81 (s, 1H), 457.58.32 (dd, J = 7.4, 0.8 Hz, 1H), 8.24-8.17 (m, 1H), 8.07-8.02 (m, 1H),7.75-7.69 (m, 1H), 7.65-7.56 (m, 1H), 7.41-7.36 (m, 1H), 7.22 (dd, J =7.4, 2.2 Hz, 1H), 6.75 (dd, J = 7.3, 0.9 Hz, 1H), 5.34 (s, 1H),3.85-2.84 (m, 4H), 2.56-2.44 (m, 2H), 2.16-2.01 (m, 1H), 1.82-1.73 (m,2H), 1.12 (s, 6H), 0.90 (d, J = 6.6 Hz, 6H). 217 (400 MHz, DMSO-d₆) δ9.14 (s, 1H), 8.81 (s, 1H), 483.6 8.36-8.29 (m, 1H), 8.24-8.17 (m, 1H),8.08-8.02 (m, 1H), 7.75-7.69 (m, 1H), 7.65-7.56 (m, 1H), 7.41-7.36 (m,1H), 7.21 (dd, J = 7.4, 2.2 Hz, 1H), 6.75 (dd, J = 7.4, 0.9 Hz, 1H),5.34 (s, 1H), 3.85-2.87 (m, 4H), 2.59-2.44 (m, 2H), 2.16-2.01 (m, 1H),1.91-1.82 (m, 2H), 1.71-1.54 (m, 8H), 0.90 (d, J = 6.6 Hz, 6H).

TABLE 2-41 218 (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.81 (s, 1H), 457.58.33 (dd, J = 7.4, 0.8 Hz, 1H), 8.20 (dd, J = 8.4, 0.9 Hz, 1H),8.08-8.02 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.56 (m, 1H), 7.43-7.36 (m,1H), 7.21 (dd, J = 7.5, 2.2 Hz, 1H), 6.75 (dd, J = 7.3, 0.9 Hz, 1H),5.33 (s, 1H), 4.04-3.38 (m, 2H), 3.12-2.77 (m, 2H), 2.59-2.41 (m, 2H),2.16-2.01 (m, 1H), 1.96-1.71 (m, 2H), 1.12-1.01 (m, 6H), 0.90 (d, J =6.6 Hz, 6H). 219 (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 9.04 (s, 1H), 431.48.32 (dd, J = 7.4, 0.8 Hz, 1H), 8.20-8.14 (m, 1H), 8.07-8.05 (m, 1H),8.05-8.02 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m, 1H), 7.22 (dd, J =7.5, 2.2 Hz, 1H), 6.50 (dd, J = 5.7, 2.4 Hz, 1H), 5.34 (s, 1H),4.27-2.77 (m, 7H), 1.96-1.77 (m, 2H), 1.06 (d, J = 5.4 Hz, 6H). 220 (400MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.92 (s, 1H), 429.5 8.36-8.29 (m, 2H),8.16-8.09 (m, 1H), 8.08-8.02 (m, 1H), 7.75-7.69 (m, 1H), 7.41-7.36 (m,1H), 7.18 (dd, J = 7.4, 2.2 Hz, 1H), 6.78 (dd, J = 5.1, 1.5 Hz, 1H),5.34 (s, 1H), 4.23-2.77 (m, 4H), 2.60 (q, J = 7.6 Hz, 2H), 1.94-1.73 (m,2H), 1.17 (t, J = 7.6 Hz, 3H), 1.07 (d, J = 5.9 Hz, 6H). 221 (500 MHz,DMSO-d₆) δ 9.23 (s, 1H), 8.90 (s, 1H), 416.8 8.38-8.28 (m, 1H),8.11-8.04 (m, 1H), 8.02-7.89 (m, 1H), 7.81-7.69 (m, 1H), 7.49-7.38 (m,1H), 7.36-7.26 (m, 1H), 6.46-6.36 (m, 1H), 5.37 (s, 1H), 3.78 (s, 3H),3.63-3.37 (m, 4H), 2.32 (s, 3H), 2.03-1.91 (m, 4H). 222 (500 MHz,DMSO-d₆) δ 15.28-14.93 (m, 1H), 444.9 13.60-13.28 (m, 1H), 11.63-11.25(m, 1H), 10.59-10.33 (m, 1H), 8.85-8.65 (m, 1H), 8.17-8.13 (m, 1H),8.13-8.07 (m, 1H), 8.01-7.95 (m, 1H), 7.90-7.84 (m, 1H), 7.00-6.93 (m,1H), 6.92-6.83 (m, 1H), 5.81-5.62 (m, 1H), 3.99 (s, 3H), 3.89-3.74 (m,1H), 3.56-3.46 (m, 2H), 3.20-3.09 (m, 1H), 2.56 (s, 3H), 1.92-1.77 (m,2H), 1.15 (s, 6H).

Test Example 1: In Vitro Antimalarial Assay

For the evaluation of the antimalarial activity of the compound of thepresent invention, K1 strain, a drug resistant strain of Plasmodiumfalciparum, and FCR3 strain, a drug sensitive strain thereof, which weregenerous gift from Professor Kiyoshi Kita of the Graduate School ofMedicine and Faculty of Medicine, the University of Tokyo, were used tomeasure the in vitro antimalarial activity of the compound against thosePlasmodium species according to the method established by Otoguro et al.(Otoguro, K., Kohana, A., Manabe, C., Ishiyama, A., Ui, H., Shiomi, K.,Yamada, H. & Omura, S.: Potent antimalarial activity of polyetherantibiotic, X-206. J. Antibiot., 54: 658-663, (2001)).

The parasites were grown based on a slightly modified method from theoriginal method reported by Trager and Jensen (Trager, W. and Jensen,J.: Human malaria parasites in continuous culture, Science, 193:673-677, (1976)), and those which were maintained and sub-cultured bythe method were used. More specifically, in a culture dish, erythrocytesinfected with the protozoa, which had been sub-cultured using a RPMI1640 medium to which 10% human plasma had been added and fresh humanerythrocytes, were diluted (hematocrit value: 2 to 5%, parasitaemia:0.25 to 1%), and were cultured at 37° C. in a mixed gas of 3% O₂-4%CO₂-93% N₂, and continuously cultured while changing the medium andadding fresh erythrocytes at 2- or 3-day intervals.

A drug susceptibility test was performed by modifying the methodestablished by Desjardins et al. (Desjardins, R. E., Canfield, C. J.,Haynes, D. E. and Chulay, J. D.: Quantitative assessment of antimalarialactivity in vitro by a semiautomated microdilution technique.Antimicrob. Agents Chemother., 16: 710-718 (1979)). More specifically,190 μL of a suspension of protozoa which had been precultured(hematocrit value: 2%, parasitaemia: 0.5 or 1%) and 10 μL of a solutionof a test compound (5% DMSO solution) serially diluted so that the finalconcentration was 12.5 to 0.0001 μM were put in each well of a 96-wellplate, and after mixing, the same was cultured for 72 hours in the abovemixed gas.

For the measurement of the growth of protozoa, the method established byMakler (Makler, M. T., Rise, J. M., Williams, J. A., Bancroft, J. E.,Piper, R. C., Gibbins, B. L. and Hinrichs, D. J.: Parasite lactatedehydrogenase as an Assay for Plasmodium falciparum drug sensitivity,Am. J. Med. Hyg., 48: 739-741 (1993)) was modified to colorimetricallydetermine parasite lactate dehydrogenase (p-LDH) using Malstat reagent(Flow Inc., USA).

More specifically, 72 hours after the culture, the 96-well plate wasdirectly frozen at −20° C. for 18 hours and melted at 37° C. to hemolyzethe protozoan-infected erythrocytes and destroy the protozoa to preparea crude enzyme solution. 100 μL of Malstat reagent and 20 μL of thecrude enzyme solution were added to and mixed in each well of another96-well plate, and after reacting for 15 minutes at room temperature, 20μL of a nitroblue tetrazolium 2 mg/mL phenazine ethosulfate 0.1mg/mL=1:1 solution was added to the respective wells, and reaction wasperformed in dark conditions at room temperature for 2 hours.

The absorbance of the blue formazan product formed by the reaction wasmeasured at a measurement wavelength of 655 nm by using a microplatereader (Labsystems, Finland) to colorimetrically determine the growth ofthe protozoa. The 50% growth inhibitory concentration for the protozoaof the compound (IC₅₀ value) was determined based on theconcentration-response curve of the compound.

(Results of Evaluation)

The compounds of the present invention showed a potent antimalarialactivity in the test for in vitro antimalarial activity. Theantimalarial activity of the representative compounds of the presentinvention against cultured Plasmodium falciparum is shown in [Table 3-1]to [Table 3-8]. The antimalarial activity is represented by symbol ***when the IC₅₀ value is less than 0.1 μM, symbol ** when 0.1 μM or moreand less than 1 μM, and symbol * when 1 μM or more and less than 10 μM.In the case where the test was not performed, NT (Not Tested) is shown.

TABLE 3-1 Tested Compound Example No. Strain K1 Strain FCR3 1 *** *** 2*** *** 3 * NT 4 ** ** 5 * * 6 ** ** 7 *** *** 8 * ** 9 ** *** 10 ****** 11 * ** 12 ** ** 13 ** *** 14 * ** 15 *** *** 16 * NT 17 *** *** 18*** *** 19 ** ** 20 ** ** 21 ** ** 22 ** ** 23 * ** 24 * NT 25 * * 26*** *** 27 ** *

TABLE 3-2 28 *** *** 29 ** ** 30 *** *** 31 ** ** 32 *** *** 33 ** ***34 *** ** 35 * * 36 * * 37 * * 38 ** ** 39 * * 40 * * 41 ** *** 42 ** **43 ** *** 44 *** *** 45 * *** 46 ** *** 47 ** *** 48 *** *** 49 * ** 50*** *** 51 * ** 52 * NT 53 ** ** 54 *** *** 55 * ** 56 * NT 57 * **

TABLE 3-3 58 *** *** 59 * NT 60 *** *** 61 * ** 62 ** ** 63 ** ** 64 ***** 65 ** ** 66 ** ** 67 ** ** 68 *** *** 69 ** *** 70 *** *** 71 ****** 72 * ** 73 ** ** 74 ** *** 75 ** *** 76 * NT 77 ** *** 78 ** *** 79** ** 80 ** ** 81 ** ** 82 ** ** 83 * ** 84 *** *** 85 * *

TABLE 3-4 86 ** ** 87 *** *** 88 *** *** 89 ** *** 90 ** *** 91 ** ***92 *** *** 93 *** *** 94 *** *** 95 *** *** 96 ** ** 97 ** ** 98 ** **99 ** ** 100 ** ** 101 * ** 102 ** ** 103 ** ** 104 * ** 105 *** *** 106*** *** 107 *** *** 108 ** *** 109 *** *** 110 ** *** 111 *** *** 112*** *** 113 *** *** 114 *** ***

TABLE 3-5 115 *** *** 116 *** *** 117 *** *** 118 *** *** 119 *** ***120 * * 121 ** *** 122 ** ** 123 ** *** 124 ** ** 125 *** *** 126 ****** 127 *** *** 128 *** *** 129 *** *** 130 *** *** 131 *** *** 132 ****** 133 *** *** 134 *** *** 135 *** *** 136 *** *** 137 *** *** 138 ***** 139 *** ***

TABLE 3-6 140 *** *** 141 ** *** 142 *** *** 143 ** * 144 ** ** 145 ***** 146 *** *** 147 *** *** 148 *** *** 149 *** *** 150 ** *** 151 ** **152 *** *** 153 *** *** 154 *** *** 155 *** *** 156 ** *** 157 *** ***158 ** *** 159 *** *** 160 *** *** 161 *** *** 162 ** *** 163 ** ***164 * ** 165 *** *** 166 *** *** 167 ** *** 168 ** ***

TABLE 3-7 169 *** *** 170 *** *** 171 ** ** 172 ** *** 173 ** ** 174 ****** 175 *** *** 176 *** *** 177 *** *** 178 *** *** 179 ** ** 180 ****** 181 *** ** 182 ** ** 183 ** ** 184 ** ** 185 *** *** 186 *** *** 187** ** 188 *** *** 189 *** *** 190 *** *** 191 ** ** 192 * ** 193 *** ***194 *** *** 195 ** ** 196 *** *** 197 ** **

TABLE 3-8 198 ** *** 199 *** *** 200 ** ** 201 ** ** 202 ** ** 203 ** **204 ** ** 205 ** ** 206 *** *** 207 ** ** 208 ** ** 209 ** **

The compounds of the present invention showed a similarly highantimalarial activity for both the drug resistant strain, K1 strain, andthe drug sensitive FCR strain. The results show that the compounds ofthe present invention have excellent efficacy for inhibiting the growthof Plasmodium species.

Test Example 2: In Vivo Antimalarial Assay

In vivo antimalarial activity of the compound of the present inventionwas determined using a mouse model infected with rodent malaria P.berghei N strain (drug sensitive strain) by slightly modifying themethod described in the above publication of Otoguro et al. (2001) andthe method reported by Peters et al. (Peters, W., Portus, J. H. andRobinson, B. L.: The chemotherapy of rodent malaria. XXII. The value ofdrug-resistant strains of P. berghei in Screening for bloodschizonticidal activity. Ann. Trop. Med. Parasitol., 69: 155-171,(1975)). The P. berghei N strain was generous gift from Dr. W. Peters(Northwick Park Institute for Medical Research, Middlesex, UnitedKingdom).

A group of three ICR male mice (Charles River Laboratories Japan, Inc.)weighing 18 to 20 g was used as a test animal. Using protozoa maintainedand sub-cultured by in vivo passage, 2×10⁶ parasite-infectederythrocytes were pre pared, and the mice were infected therewith bytail vein injection. For the therapeutic test, a 1-day suppressive testwas performed. The day of infection was defined as day 0. Two hoursafter the infection, a solution of the test compound (solvent: 3%DMSO/0.5% methylcellulose400-solution or suspension) was administeredintraperitoneally (i.p.) once to 3 times. On day 4, blood smearpreparation was prepared by collecting from the tail vein and the ratioof parasite-infected erythrocytes (parasitaemia) was investigated todetermine the therapeutic effect (inhibition percentage) based on theinfection rate of the group to which the compound was not administered.The significance test was performed by Dunnett's test.

In vivo antimalarial activities of representative compounds of thepresent invention are shown in Table 4.

TABLE 4 Tested Conpound Dosage Therapeutical Effect Significant ExampleNo. Amount (%) inhibition Differrence 28 10 mg/kg 51.4 P = 0.0055 32 10mg/kg 47.5 P = 0.0636 34 10 mg/kg 51.5 P = 0.0135 68 10 mg/kg 41.7 P =0.0656  93*  3 mg/kg 64.2 P = 0.0005 94  3 mg/kg 42.9 P = 0.0182 105  10mg/kg 41.9 P = 0.0059  106** 10 mg/kg 87.4 P = 0.0008 114  10 mg/kg 70.9P < 0.0001  142** 10 mg/kg 84.5 P < 0.0001 147* 10 mg/kg 83.4 P = 0.0227161* 10 mg/kg 64.3 P = 0.0022 165* 10 mg/kg 98.0 P = 0.0004 170  10mg/kg 92.9 P = 0.0006 174* 10 mg/kg 93.6 P = 0.0029 *Administered twice(day 0 and 1) **Administered three times (day 0, 1 and 2)

The compounds of the present invention significantly suppressed theparasitaemia with 50% inhibition in a mouse model infected with rodentmalaria P. berghei N strain compared with the vehicle control group wheninjected i.p. at 3 or 10 mg/kg once or twice, showing therapeuticeffect. The results suggest that the effective dose 50 (ED₅₀) of thecompounds of the present invention is about 3 to 10 mg/kg, indicatingthe compounds have excellent efficacy as a therapeutic agent forplasmodium infection at low doses.

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful as an agent fortreating, preventing and/or inhibiting propagation of infection withhuman infectious Plasmodium such as Plasmodium falciparum, Plasmodiumvivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi.The compound of the present invention is also useful for treating,preventing and inhibiting propagation of infection with Plasmodiumresistant to existing antimalarials such as chloroquine and fansidar.The compound may also be used as an agent for inhibiting growth ofPlasmodium in the form of a reagent for experiment and research.

The invention claimed is:
 1. A compound of the formula (I):

wherein the ring A is a 6-membered heteroaryl group having one or morenitrogen atom(s) optionally substituted with R¹, R² and R³; Z is anoptionally substituted alkoxy group, an optionally substituted aminogroup, an optionally substituted heterocyloalkyl group or an optionallysubstituted heteroaryl group; and R¹, R² and R³ are independentlyselected from the group consisting of a hydrogen atom, a halogen atom,an optionally substituted alkyl group, an optionally substitutedcycloalkyl group, an optionally substituted alkoxy group, an optionallysubstituted cycloalkyloxy group, an optionally substitutedheterocycloalkyloxy group, an optionally substituted phenoxy group, anoptionally substituted amino group, a nitro group and a hydroxy group;or pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein the ring A is an optionally substituted 6-memberedheteroaryl group containing a nitrogen atom or pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1, whereinthe ring A is an optionally substituted 6-membered heteroaryl groupcontaining two nitrogen atoms or pharmaceutically acceptable saltthereof.
 4. The compound according to claim 1, wherein the group of

is a heteroaryl group selected from the group consisting of

or pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising the compound according to claim 1 orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 6. A therapeutic agent for treating infectiondiseases of malaria plasmodium, comprising the compound according toclaim 1 or a pharmaceutically acceptable salt thereof.